Bicyclic inhibitors of protein farnesyl transferase

ABSTRACT

The present invention provide compounds of Formula I                    
     The present invention also provides a method of treating cancer and treating or preventing restenosis or atherosclerosis. Also provided by the present invention is a pharmaceutically acceptable composition containing a compound of Formula I.

This application is a division of U.S. Ser. No. 09/560,606 filed Apr.28, 2000, U.S. Pat. No. 6,265,422, which is a division of U.S. Ser. No.09/355,662 filed May 2, 1999, U.S. Pat. No. 6,133,303 filed Aug. 2,1999, which is a 371 of PCT/US98/03025 filed Feb. 11, 1998, and claimsbenefit of provisional application 60/037,504, filed Feb. 11, 1997.

FIELD OF THE INVENTION

The present invention relates to compounds that can be used to treat,prophylactically or otherwise, uncontrolled or abnormal proliferation oftissues. Specifically, the present invention relates to compounds thatinhibit the farnesyl transferase enzyme, which has been determined toactivate ras proteins that in turn activate cellular division and areimplicated in cancer, restenosis, and atherosclerosis. a

BACKGROUND OF THE INVENTION

Ras protein (or p21) has been examined extensively because mutant formsare found in 20% of most types of human cancer and greater than 50% ofcolon and pancreatic carcinomas (Gibbs J. B., Cell, 1991;65:1,Cartwright T. et al., Chimica. Oggi., 1992;10:26). These mutant rasproteins are deficient in the capability for feedback regulation that ispresent in native ras, and this deficiency is associated with theironcogenic action since the ability to stimulate normal cell divisioncannot be controlled by the normal endogenous regulatory cofactors. Therecent discovery that the transforming activity of mutant ras iscritically dependent on post-translational modifications (Gibbs J. etal., Microbiol. Rev., 1989;53:171) has unveiled an important aspect ofras function and identified novel prospects for cancer therapy.

In addition to cancer, there are other conditions of uncontrolledcellular proliferation that may be related to excessive expressionand/or function of native ras proteins. Post-surgical vascularrestenosis and atherosclerosis are such conditions. The use of varioussurgical revascularization techniques such as saphenous vein bypassgrafting, endarterectomy, and transluminal coronary angioplasty areoften accompanied by complications due to uncontrolled growth ofneointimal tissue, known as restenosis. The biochemical causes ofrestenosis are poorly understood and numerous growth factors andprotooncogenes have been implicated (Naftilan A. J. et al.,Hypertension, 1989;13:706 and J. Clin. Invest., 83:1419; Gibbons G H. etal., Hypertension, 1989;14:358; Satoh T. et al., Molec. Cell. Biol.,1993;13:3706). The fact that ras proteins are known to be involved incell division processes makes them a candidate for intervention in manysituations where cells are dividing uncontrollably. In direct analogy tothe inhibition of mutant ras related cancer, blockade of ras dependentprocesses has the potential to reduce or eliminate the inappropriatetissue proliferation associated with restenosis or atherosclerosis,particularly in those instances where normal ras expression and/orfunction is exaggerated by growth stimulatory factors. See, for example,Kohl et al., Nature Med., 1995;1(8):792-748.

Ras functioning is dependent upon the modification of the proteins inorder to associate with the inner face of plasma membranes. Unlike othermembrane-associated proteins, ras proteins lack conventionaltransmembrane or hydrophobic sequences and are initially synthesized ina cytosol soluble form. Ras protein membrane association is triggered bya series of post-translational processing steps that are signaled by acarboxyl terminal amino acid consensus sequence that is recognized byprotein farnesyl transferase (PFT). This consensus sequence consists ofa cysteine residue located four amino acids from the carboxyl terminus,followed by two lipophilic amino acids, and the C-terminal residue. Thesulfhydryl group of the cysteine residue is alkylated by farnesylpyrophosphate in a reaction that is catalyzed by protein farnesyltransferase. Following prenylation, the C-terminal three amino acids arecleaved by an endoprotease and the newly exposed alpha-carboxyl group ofthe prenylated cysteine is methylated by a methyl transferase. Theenzymatic processing of ras proteins that begins with farnesylationenables the protein to associate with the cell membrane. Mutationalanalysis of oncogenic ras proteins indicate that thesepost-translational modifications are essential for transformingactivity. Replacement of the consensus sequence cysteine residue withother amino acids gives a ras protein that is no longer farnesylated,fails to migrate to the cell membrane and lacks the ability to stimulatecell proliferation (Hancock J. F. et al., Cell, 1989;57:1617; Schafer WR. et al., Science, 1989;245:379; Casey P. J., Proc. Natl. Acad. Sci.USA, 1989,86:8323).

Recently, protein farnesyl transferases (PFTs), also referred to asfarnesyl proteintransferases (FPTs), have been identified and a specificPFT from rat brain was purified to homogeneity (Reiss Y et al., Bioch.Soc. Trans., 1992;20:487-88). The enzyme was characterized as aheterodimer composed of one alpha-subunit (49 KDa) and one beta-subunit(46 KDa), both of which are required for catalytic activity. High levelexpression of mammalian PFT in a baculovirus system and purification ofthe recombinant enzyme in active form has also been accomplished (Chen W-J. et al., J. Biol. Chem., 1993;268:9675).

In light of the foregoing, the discovery that the function of oncogenicras proteins is critically dependent on their post-translationalprocessing provides a means of cancer chemotherapy through inhibition ofthe processing enzymes. The identification and isolation of a proteinfarnesyl transferase that catalyzes the addition of a farnesyl group toras proteins provides a promising target for such intervention. Rasfarnesyl transferase inhibitors have been shown to have anticanceractivity in several recent articles.

Ras inhibitor agents act by inhibiting farnesyl transferase, the enzymeresponsible for the post-translational modification of the ras proteinwhich helps to anchor the protein product of the ras gene to the cellmembrane. The role of the ras mutation in transducing growth signalswithin cancer cells relies on the protein being in the cell membrane sowith farnesyl transferase inhibited, the ras protein will stay in thecytosol and be unable to transmit growth signals: these facts arewell-known in the literature.

A peptidomimetic inhibitor of farnesyl transferase B956 and its methylester B1086 at 100 mg/kg have been shown to inhibit tumor growth by EJ-1human bladder carcinoma, HT1080 human fibrosarcoma and human coloncarcinoma xenografts in nude mice (Nagasu T. et al., Cancer Res.,1995;55:5310-5314). Furthermore, inhibition of tumor growth by B956 hasbeen shown to correlate with inhibition of ras posttranslationalprocessing in the tumor. Other ras farnesyl transferase inhibitors havebeen shown to specifically prevent ras processing and membranelocalization and are effective in reversing the transformed phenotype ofmutant ras containing cells (Sepp-Lorenzino L. et al., Cancer Res.,1995;55:5302-5309).

In another report (Sun J. et al., Cancer Res., 1995;55:4243-4247), a rasfarnesyl transferase inhibitor FTI276 has been shown to selectivelyblock tumor growth in nude mice of a human lung carcinoma with K-rasmutation and p53 deletion. In yet another report, daily administrationof a ras farnesyl transferase inhibitor L-744,832 caused tumorregression of mammary and salivary carcinomas in ras transgenic mice(Kohl et al., Nature Med., 1995;1(8):792-748). Thus, ras farnesyltransferase inhibitors have benefit in certain forms of cancer,particularly those dependent on oncogenic ras for their growth. However,it is well-known that human cancer is often manifested when severalmutations in important genes occurs, one or more of which may beresponsible for controlling growth and metastases. A single mutation maynot be enough to sustain growth and only after two of three mutationsoccur, tumors can develop and grow. It is therefore difficult todetermine which of these mutations may be primarily driving the growthin a particular type of cancer. Thus, ras farnesyl transferaseinhibitors can have therapeutic utility in tumors not solely dependenton oncogenic forms of ras for their growth. For example, it has beenshown that various ras FT-inhibitors have antiproliferative effects invivo against tumor lines with either wild-type or mutant ras(Sepp-Lorenzino, supra.). In addition, there are several ras-relatedproteins that are prenylated. Proteins such as R-Ras2/TC21 areras-related proteins that are prenylated in vivo by both farnesyltransferase and geranylgeranyl transferase I (Carboni et al., Oncogene,1995;10: 1905-1913). Therefore, ras farnesyl transferase inhibitorscould also block the prenylation of the above proteins and thereforewould then be useful in inhibiting the growth of tumors driven by otheroncogenes.

With regard to the restenosis and vascular proliferative diseases, ithas been shown that inhibition of cellular ras prevents smooth muscleproliferation after vascular injury in vivo (Indolfi C. et al., NatureMed., 1995;1(6):541-545). This report definitively supports a role forfarnesyl transferase inhibitors in this disease, showing inhibition ofaccumulation and proliferation of vascular smooth muscle.

SUMMARY OF THE INVENTION

The present invention provides compounds having the Formula I

wherein Q is O, —NOR,—N—NRR, —NOCH₂CO₂R^(a),

L is hydrogen,

each R^(a) or R^(b) is independently hydrogen, C₁-C₆ alkyl, C₂-C₆alkenyl, phenyl, or substituted phenyl, or R^(a) and R^(b) along withthe carbon atom to which they are bonded form a C₃-C₆ cycloalkyl ring;

each R is independently hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, benzyl,C₂-C₆ alkenyl, phenyl, or substituted phenyl;

Each - - - is a bond or absent;

P is N,

X is CH₂, CH₂O, CH₂S, CH₂SO, CH₂SO₂, CH₂NR, or

Z is hydrogen when L is

and

Z is —NRR, —R, —OR, —SR, —(CH₂)_(n)E, —O(CH₂)_(n)E, —NR(CH₂)_(n)E,—S(CH₂)_(n)E,

—N¹-piperidinyl, —N¹-piperazinyl[N⁴—R], —N-pyrrolidinyl, —N-morpholino,—N-thiomorpholino, —N-hexahydroazepine, or an amino acid having thestructure

when L is

where A is a side chain of the amino acid glycine, alanine, valine,leucine, isoleucine, phenylalanine, proline, serine, threonine,tyrosine, asparagine, glutamine, lysine, arginine, tryptophan,histidine, cysteine, methionine, aspartic acid, or glutamic acid;

E is hydrogen, halogen, —CO₂R, —CONRR, —CN, —NO₂, C₁-C₆ perfluoroalkyl,C₁-C₆ perfluoroalkoxy, acetyl, —OR, —SR, —NRR, —N¹-piperidinyl,—N¹-piperazinyl[N⁴—R], —N-pyrrolidinyl, —N-morpholino,—N-thiomorpholino, —N-hexahydroazepine, aryl, heteroaryl, substitutedaryl, or substituted heteroaryl;

each E′ is independently hydrogen, halogen, —NO₂, —NRR, —R, —OR,—S(O)_(α)R,

each n is independently 0 to 5 inclusive;

each α is independently 0, 1, or 2;

each m is independently 0, 2, 3, 4, or 5;

Y is CH₂, NR, O, SO, SO₂, or S;

A′ is aryl, heteroaryl, substituted aryl, substituted heteroaryl, C₁-C₆alkyl, C₁-C₆ substituted alkyl,

C₃-C₆ cycloalkyl or C₃-C₆ substituted cycloalkyl, provided anysubstituents are not —NO₂;

B is pyrrolyl, substituted pyrrolyl, imidazolyl, substituted imidazolyl,oxazolyl, substituted oxazolyl, thiazolyl, substituted thiazolyl,

—NR¹—(CH₂)_(n)—(CHX³)—(CH₂)_(n)—SR¹,

—S—(CH₂)_(n)—(CHX³)—(CH₂)_(n)—SR¹, or

—(CH₂)_(n)—(CHX³)—(CH₂)_(n)—SR¹;

X¹ is S or NR¹;

X² is NR¹ or CH₂;

R¹ is hydrogen or C₁-C₆ alkyl;

X³ is hydrogen —NR¹R¹ or —C₁-C₆ alkyl, and the pharmaceuticallyacceptable salts, esters, amides, and prodrugs thereof, provided thatthe compound is not 5-(2-imidazole-1-yl-ethoxy)-indan-1-one.

In a preferred embodiment of the compounds of Formula I, Q is O.

In another preferred embodiment of the compounds of Formula I, X is—CH₂CH₂.

In another preferred embodiment of the compounds of Formula I, E′ ishydrogen.

In another preferred embodiment of the compounds of Formula I, P is CH.

In another preferred embodiment of the compounds of Formula I, Y is O.

In another preferred embodiment of the compounds of Formula I, L ishydrogen.

In another preferred embodiment of the compounds of Formula I, B isimidazolyl or substituted imidazolyl.

In another preferred embodiment of the compounds of Formula I,

L is

Z is hydrogen, and A′ is phenyl, substituted phenyl, pyridyl,substituted pyridyl, thienyl, substituted thienyl, furyl, substitutedfuryl, naphthyl, or substituted naphthyl.

Also provided by the present invention are compounds having the FormulaII

wherein Q is O, —NOR, —N—NRR, —NOCH₂CO₂R^(a),

each R^(a) or R^(b) is independently hydrogen, C₁-C₆ alkyl, C₂-C₆alkenyl, phenyl, or substituted phenyl, or R^(a) and R^(b) along withthe carbon atom to which they are bonded form a C₃-C₆ cycloalkyl ring;

each R is independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆cycloalkyl, benzyl, C₂-C₆ alkenyl, phenyl, or substituted phenyl;

E is hydrogen, halogen, —CO₂R, —CONRR, —CN, —NO₂, C₁-C₆ perfluoroalkyl,C₁-C₆ perfluoroalkoxy, acetyl, —OR, —SR, —NRR, —N¹-piperidinyl,—N¹-piperazinyl[N⁴—R], —N-pyrrolidinyl, —N-morpholino,—N-thiomorpholino, —N-hexahydroazepine, aryl, heteroaryl, substitutedaryl,

or substituted heteroaryl; each E′ is independently hydrogen, halogen,—NO₂, —NRR, —R, —OR, —S(O)_(α)R, —S(CH₂)_(n)E, —(CH₂)_(n)E,—O—(CH₂)_(n)E, —NR(CH₂)_(n)E,

each n is independently 0 to 5 inclusive;

each α is independently 0, 1, or 2;

each m is independently 0, 2, 3, 4, or 5;

Y is CH₂, NR, O, SO, SO₂, or S;

B is pyrrolyl, substituted pyrrolyl, imidazolyl, substituted imidazolyl,oxazolyl, substituted oxazolyl, thiazolyl, substituted thiazolyl,

—NR¹—(CH₂)_(n)—(CHX³)—(CH₂)_(n)—SR¹, —S—(CH₂)_(n)—(CHX³)—(CH₂)_(n)—SR¹,or

—(CH₂)_(n)—(CHX³)—(CH₂)_(n)—SR¹;

X¹ is S or NR¹;

X² is NR¹ or CH₂;

R¹ is hydrogen or C₁-C₆ alkyl;

X³ is hydrogen, —NR¹R¹, or —C₁-C₆ alkyl, and the pharmaceuticallyacceptable salts, esters, amides and prodrugs thereof

In a preferred embodiment of the compounds of Formula II, Q is O.

In another preferred embodiment of the compounds of Formula II, E′ ishydrogen.

In another preferred embodiment of the compounds of Formula II, Y is O.

In another preferred embodiment of the compounds of Formula II, B isimidazolyl or substituted imidazolyl.

Also provided by the present invention are compounds having the FormulaIII

wherein Q is O, —NOR, or —N—NRR;

Z is hydrogen when - - - is absent and Z is —NRR, —R, —OR, —SR,—(CH₂)_(n)E,

—O(CH₂)_(n)E, —NR(CH₂)_(n)E, —S(CH₂)_(n)E, —N¹-piperidinyl,

—N¹-piperazinyl[N⁴—R], —N-pyrrolidinyl, —N-morpholino,

—N-thiomorpholino, —N-hexahydroazepine, or an amino acid having thestructure

where A is a side chain of the amino acid glycine, alanine, valine,leucine, isoleucine, phenylalanine, proline, serine, threonine,tyrosine, asparagine, glutamine, lysine, arginine, tryptophan,histidine, cysteine, methionine, aspartic acid, or glutamic acid;

when - - - is a bond;

each R^(a) or R^(b) is independently hydrogen, C₁-C₆ alkyl, C₂-C₆alkenyl, phenyl, or substituted phenyl, or R^(a) and R^(b) along withthe carbon atom to which they are bonded form a C₃-C₆ cycloalkyl ring;

each R is independently hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, benzyl,C₂-C₆ alkenyl, phenyl, or substituted phenyl;

Each - - - is a bond or absent;

E is hydrogen, halogen, —CO₂R, —CONRR, —CN, —NO₂, C₁-C₆ perfluoroalkyl,C₁-C₆ perfluoroalkoxy, acetyl, —OR, —SR, —NRR, —N¹-piperidinyl,—N¹-piperazinyl[N⁴—R], —N-pyrrolidinyl, —N-morpholino,—N-thiomorpholino, —N-hexahydroazepine, aryl, heteroaryl, substitutedaryl, or substituted heteroaryl;

E′ is hydrogen, halogen, —NO₂, —NRR, —R, —OR, —S(O)_(α)R, —S(CH₂)_(n)E,—(CH₂)_(n)E, —O—(CH₂)_(n)E, —NR(CH₂)_(n)E, —CO₂R, —CONRR,

each n is independently 0 to 5 inclusive;

each a is independently 0, 1, or 2;

each m is independently 0, 2, 3, 4, or 5;

Y is CH₂, NR, O, or S;

A′ is aryl, heteroaryl, substituted aryl or substituted heteroaryl,C₃-C₆ cycloalkyl or C₃-C₆ substituted cycloalkyl, provided that anysubstituents are not —NO₂;

B is pyrrolyl, substituted pyrrolyl, imidazolyl, substituted imidazolyl,oxazolyl, substituted oxazolyl, thiazolyl, substituted thiazolyl,

—NR¹—(CH₂)_(n)—(CHX³)—(CH₂)_(n)—SR¹,

—S—(CH₂)_(n)—(CHX³)—(CH₂)_(n)—SR¹, or

—(CH₂)_(n)—(CHX³)—(CH₂)_(n)—SR¹;

X¹ is S or NR¹;

X² is NR¹ or CH₂;

R¹ is hydrogen or C₁-C₆ alkyl;

X³ is hydrogen, —NR¹R¹ or —C₁-C₆ alkyl, and the pharmaceuticallyacceptable salts, esters, amides, and prodrugs thereof

In a preferred embodiment of the compounds of Formula III, Q is O.

In a preferred embodiment of the compounds of Formula III, E′ ishydrogen.

In a preferred embodiment of the compounds of Formula III, Y is O.

In a preferred embodiment of the compounds of Formula III, A′ is phenyl,substituted phenyl, pyridyl, substituted pyridyl, thienyl, substitutedthienyl, furyl, substituted furyl, naphthyl, or substituted naphthyl.

In a more preferred embodiment of the compound of Formula III, A′ isphenyl, substituted phenyl, thienyl, substituted thienyl, furyl, orsubstituted furyl.

In a preferred embodiment of the compounds of Formula III, B isimidazolyl or substituted imidazolyl.

In a most preferred embodiment, the present invention provides thecompounds:

6-(2-Imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one;

6-[2-(2-Methyl-imidazole-1-yl)-ethoxy]-3,4-dihydro-2H-naphthalen-1-one;

6-(2-Imidazole-1-yl-ethoxy)-2-pyridin-2-ylmethylene-3,4-dihydro-2H-naphthalen-1-one;

6-(2-Imidazole-1-yl-ethoxy)-2-(4-methylsulfanyl-benzylidene)-3,4-dihydro-2H-naphthalen-1-one;

2-(4-Bromo-benzylidene)-6-(2-imiddazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one;

6-(2-Imidazole-1-yl-ethoxy)-2-pyridin-4-ylmethylene-3,4-dihydro-2H-naphthalen-1-one;

6-(2-Iridazole-1-yl-ethoxy)-2-(4-nitro-benzylidene)-3,4-dihydro-2H-naphthalen-1-one;

2-[4-(2-Diethylamino-ethoxy)-benzylidene]-6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one;

2-Benzylidene-6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one;

6-(2-Imidazole-1-yl-ethoxy)-2-(4-methylsulfanyl-benzyl)-3,4-dihydro-2H-naphthalen-1-one;

6-(2-Imidazole-1-yl-ethoxy)-2-thiophen-3-ylmethylene-3,4-dihydro-2H-naphthalen-1-one;

4-[6-(2-Imidazole-1-yl-ethoxy)-1-oxo-3,4-dihydro-1H-naphthalen-2-ylidenemethyl]-benzoicacid;

2-(4-Bromo-benzyl)-6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one;

6-(2-Imidazole-1-yl-ethoxy)-2-thiophen-2-ylmethylene-3,4-dihydro-2H-naphthalen-1-one;

6-(2-Imidazole-1-yl-ethoxy)-2-naphthalen-1-ylmethylene-3,4-dihydro-2H-naphthalen-1-one;

2-Furan-2-ylmethylene-6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one;

2-(4-Bromo-thiophen-2-ylmethylene)-6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one;

2-(5-Chloro-thiophen-2-ylmethylene)-6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one;

6-(2-Imidazole-1-yl-ethoxy)-2-(5-methylsulfanyl-thiophen-2-ylmethylene)-3,4-dihydro-2H-naphthalen-1-one;

6-(2-Imidazole-1-yl-ethoxy)-2-(3-phenoxy-thiophen-2-ylmethylene)-3,4-dihydro-2H-naphthalen-1-one;

2-[2,2′]Bithiophenyl-5-ylmethylene-6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one;

2-Furan-3-ylmethylene-6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one;

6-(2-Imidazole-1-yl-ethoxy)-2-(4-methoxy-benzylidene)-3,4-dihydro-2H-naphthalen-1-one;

6-(2-Imidazole-1-yl-ethoxy)-2-(4-amino-benzylidene)-3,4-dihydro-2H-naphthalen-1-one;

6-(2-Imidazole-1-yl-ethoxy)-2-(2-methoxy-benzylidene)-3,4-dihydro-2H-naphthalen-1-one;

6-(2-Imidazole-1-yl-ethoxy)-2-thiazol-2-ylmethylene-3,4-dihydro-2H-naphthalene-1-one;

6-[2-(1H-Imidazole-4-yl)-ethoxy]-3,4-dihydro-2H-naphthalen-1-one;

6-[2-(1H-Imidazole-4-yl)-ethoxy]-2-thiophen-3-ylmethylene-3,4-dihydro-2H-naphthalen-1-one;

6-[2-(1H-Imidazole-4-yl)-ethoxy]-2-thiophen-2-ylmethylene-3,4-dihydro-2H-naphthalen-1-one;

2-Benzylidene-6-[2-(1H-imidazole-4-yl)-ethoxy]-3,4-dihydro-2H-naphthalen-1-one;

6-[2-(1H-Imidazole-4-yl)-ethoxy]-2-(4-methylsulfanyl-benzylidene)-3,4-dihydro-2H-naphthalen-1-one;

6-[2-(1H-Imidazole-4-yl)-ethoxy]-2-(5-methylsulfanyl-thiophen-2-ylmethylene)-3,4-dihydro-2H-naphthalen-1-one;

4-{6-[2-(1H-Imidazole-4-yl)-ethoxy]-1-oxo-3,4-dihydro-1H-naphthalen-2-ylidenemethyl}-benzamide,monohydrochloride;

N,N-Diethyl-4- {6-[2-(1H-imidazole-4-yl)-ethoxy]-1-oxo-3,4-dihydro-1H-naphthalen-2-ylidenemethyl}-benzamide,monohydrochloride;

4-{6-[2-(1H-Imidazole-4-yl)-ethoxy]-1-oxo-3,4-dihydro-1H-naphthalen-2-ylidenemethyl}-benzoicacid, ditrifluoroacetate;

2-(5-Chloro-thiophen-2-ylmethylene)-6-[2-(1H-imidazole-4-yl)-ethoxy]-3,4-dihydro-2H-naphthalen-1-one,hydrochloride;

6-[2-(1H-Imidazole4-yl)-ethoxy]-2-(5-methyl-thiophen-2-ylmethylene)-3,4-dihydro-2H-naphthalen-1-one;

6-[2-(1H-Imidazole-4-yl)-ethoxy]-2-(3-methyl-thiophen-2-ylmethylene)-3,4-dihydro-2H-naphthalen-1-one;

6-[2-(1H-Imidazole-4-yl)-ethoxy]-2-(1-phenyl-ethylidene)-3,4-dihydro-2H-naphthalen-1-one;

2-Furan-2-ylmethylene-6-[2-(1H-imiddazole-4-yl)-ethoxy]-3,4-dihydro-2H-naphthalen-1-one;

2-(4-Bromo-benzylidene)-6-[2-(1H-imidazole-4-yl)-ethoxy]-3,4-dihydro-2H-naphthalen-1-one;

5-{6-[2-(1H-Imidazol-4-yl)-ethoxy]-1-oxo-3,4-dihydro-1H-naphthalen-2-ylidenemethyl}-thiophene-2-carboxylicacid;

6-[3-(1H-Imidazole-4-yl)-propoxy]-3,4-dihydro-2H-naphthalen-1-one;

2-(Hydroxy-thiazol-2-yl-methyl)-6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one;

(E,E)-6-(2-Imidazole-1-yl-ethoxy)-2-(3-phenyl-allylidene)-3,4-dihydro-2H-naphthalen-1-one;

2-[(E)-1-Cyclohexylmethylidene]-6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone,hydrochloride;

6-[2-(1H-1-Imidazolyl)ethoxyl-7-methyl-2-[(E)-1-(2-thienyl)methylidene]-1,2,3,4-tetrahydro-1-naphthalenone;

6-[2-(1H-1-Imidazolyl)ethoxy]-5-methyl-1,2,3,4-tetrahydro-1-naphthalenone;

6-[2-(1H-1-Imidazolyl)ethoxy]-5-methyl-2-[(E)-1-(2-thienyl)methylidene]-1,2,3,4-tetrahydro-1-naphthalenone;

7-[2-(1H-1-Imidazolyl)ethoxy]-3-[(E)-1-(2-thienyl)methylidene]-1,2,3,4-tetrahydro-4-quinolinone;

7-[2-(1H-1-Imidazolyl)ethoxy]-4H-4-chromenone;

7-[2-(1H-1-Imidazolyl)ethoxy]-4-chromanone;

7-[2-(1H-1-Imidazolyl)ethoxy]-3-[(E)-1-(2-thienyl)methylidene]-4-chromanone;

6-[2-(1H-1-Imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone oxime;

[6-(2-Imidazol-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-ylideneaminooxy]-aceticacid;

2-[6-(2-Imidazol-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-ylideneaminooxy]-N-(2-methyl-2-phenyl-propyl)-acetamide;

2-[(E)-1-(3-Chlorophenyl)methylidene]-6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone;

2-[(E)-1-(4-Chlorophenyl)methylidene]-6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone;

2-[(E)-1-(1,3-Benzodioxol-5-yl)methylidene]-6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone;

2-[(E)-1-(4-Fluorophenyl)methylidene]-6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone;

2-[(E)-1-(2,3-Dichlorophenyl)methylidene]-6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone;

2-[(E)-1-(2,6-Dichlorophenyl)methylidene]-6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone;

2-[(E)-1-(3,4-Dichlorophenyl)methylidene]-6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone;

2-[(E)-1-(3,5-Dichlorophenyl)methylidene]-6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone;

2-[(E)-1-(2,5-Dimethoxyphenyl)methylidene]-6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone;

2-[(E)-1-(2,3-Dimethoxyphenyl)methylidene]-6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone;

6-[2-(1H-1-Imidazolyl)ethoxy]-2-(E)-1-[2-(trifluoromethyl)phenyl]methylidene-1,2,3,4-tetrahydro-1-naphthalenone;

6-[2-(1H-1-Imidazolyl)ethoxy]-2-[(E)-1-(2,4,6-trimethoxyphenyl)methylidene]-1,2,3,4-tetrahydro-1-naphthalenone;

6-[2-(1H-1-Imidazolyl)ethoxy]-2-[(E)-1-(2,3,4-trimethoxyphenyl)methylidene]-1,2,3,4-tetrahydro-1-naphthalenone;

6-[2-(1H-1-Imidazolyl)ethoxy]-2-[(E)-1-(4-iodophenyl)methylidene]-1,2,3,4-tetrahydro-1-naphthalenon;

2-(E)-1-[4-(Dimethylamino)phenyl]methylidene-6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone;

2-(E)-1-[4-(tert-Butyl)phenyl]methylidene-6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone;

6-[2-(1H-1-Imidazolyl)ethoxy]-2-[(E)-1-(3-methoxyphenyl)methylidene]-1,2,3,4-tetrahydro-1-naphthalenone;

6-[2-(1H-1-Imidazolyl)ethoxy]-2-[(E)-1-(3-methylphenyl)methylidene]-1,2,3,4-tetrahydro-1-naphthalenone;

2-(E)-1-[4-(Diethylamino)phenyl]methylidene-6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone,di-trifluoroacetic acid salt;

7-[2-(1H-1-Imidazolyl)ethoxy]-2-phenyl-chromanone;

7-[2-(1H-1-Imidazolyl)ethoxy]-2-phenyl-4H-4-chromenone;

6-[2-(1H-1-Imidazolyl)propoxy]-1,2,3,4-tetrahydro-1-naphthalenone;

6-[2-(1H-1-Imidazolyl)propoxy]-2-[(E)-1-(2-thienyl)methylidene]-1,2,3,4-tetrahydro-1-naphthalenone;

6-[2-(1H-1-Imidazolyl)-1-phenylethoxy]-1,2,3,4-tetrahydro-1-naphthalenone;

6-(2-Imidazol-1-yl-1-phenyl-ethoxy)-2-thiophen-2-ylmethylene-3,4-dihydro-2H-naphthalen-1-one;

2-[6-(2-Imidazol-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-ylideneaminooxy]-N-(1-phenyl-cyclobutylmethyl)-acetamide;and

7-[2-(1H-Imidazolyl)ethoxy]-2,2-dimethyl-4-chromanone.

The present invention also provides a pharmaceutically acceptablecomposition that comprises a compound of Formula I, II, III, or IV

The present invention also provides a method of treating or preventingrestenosis, the method comprising administering to a patient havingrestenosis or at risk of having restenosis a therapeutically effectiveamount of Formula I, II, III, or IV

The present invention also provides a method of treating cancer, themethod comprising administering to a patient having cancer atherapeutically effective amount of a compound of Formula I, II, III, orIV In a preferred embodiment of the method of treating cancer, thecancer is lung, colon, pancreatic, thyroid, or bladder cancer.

The present invention also provides a method of treatingatherosclerosis, the method comprising administering to a patient havingatherosclerosis a therapeutically effective amount of a compound ofFormula I, II, III, or IV

Also provided is a method of treating or preventing restenosis oratherosclerosis or treating cancer, the method of comprisingadministering to a patient having restenosis or atherosclerosis, or atrisk of having restenosis or atherosclerosis, or having cancer atherapeutically effective amount of a compound of Formula I

wherein Q is O, —NOR, —N—NRR, —NOCH₂CO₂R^(a),

each R^(a) or R^(b) is independently hydrogen, C₁-C₆ alkyl, C₂-C₆alkenyl, phenyl, or substituted phenyl, or R^(a) and R^(b) along withthe carbon atom to which they are bonded form a C₃-C₆ cycloalkyl ring;

each R is independently hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, benzyl,C₂-C₆ alkenyl, phenyl, or substituted phenyl;

Each - - - is a bond or absent;

P is N

X is CH₂, CH₂O, CH₂S, CH₂SO, CH₂SO₂, CH₂NR, or

Z is hydrogen when L is

and

Z is —NRR, —R, —OR, —SR, —(CH₂)_(n)E, O(CH₂)_(n)E, —NR(CH₂)_(n)E,—S(CH₂)_(n)E, —N¹-piperidinyl, —N¹-piperazinyl[N⁴—R], —N-pyrrolidinyl,—N-morpholino, —N-thiomorpholino, —N-hexahydroazepine, or an amino acidhaving the structure

when L is

where A is a side chain of the amino acid glycine, alanine, valine,leucine, isoleucine, phenylalanine, proline, serine, threonine,tyrosine, asparagine, glutamine, lysine, arginine, tryptophan,histidine, cysteine, methionine, aspartic acid, or glutamic acid;

E is hydrogen, halogen, —CO₂R, —CONRR, —CN, —NO₂, C₁-C₆ perfluoroalkyl,C₁-C₆ perfluoroalkoxy, acetyl, —OR, —SR, —NRR, —N¹-piperidinyl,—N¹-piperazinyl[N⁴—R], —N-pyrrolidinyl, —N-morpholino,—N-thiomorpholino, —N-hexahydroazepine, aryl, heteroaryl, substitutedaryl, or substituted heteroaryl;

each E′ is independently hydrogen, halogen, —NO₂, —NRR, —R, —OR,—S(O)_(α)(R,

each n is independently 0 to 5 inclusive;

each a is independently 0, 1, or 2;

each m is independently 0, 2, 3, 4, or 5;

Y is CH₂, NR, O, SO, SO₂, or S.;

A′ is aryl, heteroaryl, substituted aryl or substituted heteroaryl,C₁-C₆ substituted alkyl,

C₃-C₆ cycloalkyl or C₃-C₆ substituted cycloalkyl;

B is pyrrolyl, substituted pyrrolyl, imidazolyl, substituted imidazolyl,oxazolyl, substituted oxazolyl, thiazolyl, substituted thiazolyl,

—NR1—(CH₂)_(n)—(CHX³)—(CH₂)_(n)—SR¹,

—S—(CH₂)_(n)—(CHX³)—(CH₂)_(n)—SR¹, or

—(CH₂)_(n)—(CHX³)—(CH₂)_(n)—SR¹;

X¹ is S or NR¹;

X² is NR¹ or CH₂;

R¹ is hydrogen or C₁-C₆ alkyl;

X³ is hydrogen —NR¹R¹ or —C₁-C₆ alkyl, and the pharmaceuticallyacceptable salts, esters, amides, and prodrugs thereof

Also provided are compounds having the Formula IV

wherein

each J is independently C₁-C₆ alkyl;

Y is CH₂, NR, O, SO, SO₂, or S;

each m is independently 0, 2, 3, 4, or 5;

each R^(a) or R^(b) is independently hydrogen, C₁-C₆ alkyl, C₂-C₆alkenyl, phenyl, substituted phenyl, or R^(a) and R^(b) together withthe carbon atom to which they are bonded form a C₃-C₆ cycloalkyl ring;

B is pyrrolyl, substituted pyrrolyl, imidazolyl, substituted imidazolyl,oxazolyl, substituted oxazolyl, thiazolyl, substituted thiazolyl,

—NR¹—(CH₂)_(n)—(CHX³)—(CH₂)_(n)—SR¹,

—S—(CH₂)_(n)—(CHX³)—(CH₂)_(n)—SR¹, or

—(CH₂)_(n)—(CHX³)—(CH₂)_(n)—SR¹;

X¹ is S or NR¹;

X² is NR¹ or CH₂;

R¹ is hydrogen or C₁-C₆ alkyl;

X³ is hydrogen —NR¹R¹ or —C₁-C₆ alkyl;

X is CH₂ or —O—;

Q is O, —NOR, —N—NRR, —NOCH₂CO₂R^(a),

each R is independently hydrogen, C₁—C₆ alkyl, C₃-C₆ cycloalkyl, benzyl,C₂-C₆ alkenyl, phenyl, or substituted phenyl;

each E′ is independently hydrogen, halogen, —NO₂, —NRR, —R, —OR,—S(O)_(α)R,

each α is independently 0, 1, or 2;

each n is independently 0 to 5;

E is hydrogen, halogen, —CO₂R, —CONRR, —CN, —NO₂, C₁-C₆ perfluoroalkyl,C₁-C₆ perfluoroalkoxy, acetyl, —OR, —SR, —NRR, —N¹-piperidinyl,—N¹-piperazinyl[N⁴—R], —N-pyrrolidinyl, —N-morpholino,—N-thiomorpholino, —N-hexahydroazepine, aryl, heteroaryl, substitutedaryl, or substituted heteroaryl;

and the pharmaceutically acceptable salts, esters, amides, and prodrugsthereof

Also provided is a pharmaceutically acceptable composition thatcomprises a compound of Formula IV

Also provided is a method of treating or preventing restenosis oratherosclerosis, the method comprising administering to a patient havingrestenosis or atherosclerosis or at risk of having restenosis oratherosclerosis a therapeutically effective amount of a compound ofFormula IV

Also provided is a method of treating cancer, the method comprisingadministering to a patient having cancer a therapeutically effectiveamount of a compound of Formula IV

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds having the Formula I

wherein Q is O, —NOR, —N—NRR, —NOCH₂CO₂R^(a),

L is hydrogen,

each R^(a) or R^(b) is independently hydrogen, C₁-C₆ alkyl, C₂-C₆alkenyl, phenyl, or substituted phenyl, or R^(a) and R^(b) along withthe carbon atom to which they are bonded form a C₃-C₆ cycloalkyl ring;

each R is independently hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, benzyl,C₂-C₆ alkenyl, phenyl, or substituted phenyl;

Each - - - is a bond or absent;

X is CH₂, CH₂O, CH₂S, CH₂SO, CH₂SO₂, CH₂NR, or

Z is hydrogen when L is

and

Z is —NMR, —R, —OR, —SR, —(CH₂)_(n)E, —O(CH₂)_(n)E, —NR(CH₂)_(n)E,—S(CH₂)_(n)E, —N¹-piperidinyl, —N¹-piperazinyl[N⁴—R], —N-pyrrolidinyl,—N-morpholino, —N-thiomorpholino, —N-hexahydroazepine, or an amino acidhaving the structure

when L is

where A is a side chain of the amino acid glycine, alanine, valine,leucine, isoleucine, phenylalanine, proline, serine, threonine,tyrosine, asparagine, glutamine, lysine, arginine, tryptophan,histidine, cysteine, methionine, aspartic acid, or glutamic acid;

E is hydrogen, halogen, —CO₂R, —CONRR, —CN, —NO₂, C₁-C₆ perfluoroalkyl,C₁-C₆ perfluoroalkoxy, acetyl, —OR, —SR, —NRR, —N¹-piperidinyl,—N¹-piperazinyl[N⁴—R], —N-pyrrolidinyl, —N-morpholino,—N-thiomorpholino, —N-hexahydroazepine, aryl, heteroaryl, substitutedaryl, or substituted heteroaryl;

each E′ is independently hydrogen, halogen, —NO₂, —NRR, —R, —OR,—S(O)_(α)R,

each n is independently 0 to 5 inclusive;

each α is independently 0, 1, or 2;

each a is independently 0, 2, 3, 4, or 5;

Y is CH₂, NR, O, SO, SO₂, or S;

A′ is aryl, heteroaryl, substituted aryl, substituted heteroaryl, C₁-C₆alkyl, C₁-C₆ substituted alkyl,

C₃-C6 cycloalkyl or C₃-C₆ substituted cycloalkyl, provided anysubstituents are not —NO₂;

B is pyrrolyl, substituted pyrrolyl, imidazolyl, substituted imidazolyl,oxazolyl, substituted oxazolyl, thiazolyl, substituted thiazolyl,

—NR¹—(CH₂)_(n)—(CHX³)—(CH₂)_(n)—SR¹,

—S—(CH₂)_(n)—(CHX³)—(CH₂)_(n)—SR¹, or

—(CH₂)_(n)—(CHX³)—(CH₂)_(n)—SR¹;

X¹ is S or NR¹;

X² is NR¹ or CH₂;

R¹ is hydrogen or C₁-C₆ alkyl;

X³ is hydrogen —NR¹R¹ or —C₁-C₆ alkyl, and the pharmaceuticallyacceptable salts, esters, amides, and prodrugs thereof, provided thatthe compound is not 5-(2-imidazole-1-yl-ethoxy)-indan-1-one.

Also provided by the present invention are compounds having the FormulaII

wherein Q is O, —NOR, —N—NRR, —NOCH₂CO₂R^(a),

each R^(a) or R^(b) is independently hydrogen, C₁-C₆ alkyl, C₂-C₆alkenyl, phenyl, or substituted phenyl, or R^(a) and R^(b) along withthe carbon atom to which they are bonded form a C₃-C₆ cycloalkyl ring;

each R is independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆cycloalkyl, benzyl, C₂-C₆ alkenyl, phenyl, or substituted phenyl;

E is hydrogen, halogen, —CO₂R, —CONRR, —CN, —NO₂, C₁-C₆ perfluoroalkyl,C₁-C₆ perfluoroalkoxy, acetyl, —OR, —SR, —NRR, —N¹-piperidinyl,—N¹-piperazinyl[N⁴—R], —N-pyrrolidinyl, —N-morpholino,—N-thiomorpholino, —N-hexahydroazepine, aryl, heteroaryl, substitutedaryl, or substituted heteroaryl;

each E′ is independently hydrogen, halogen, —NO₂, —NRR, —R, —OR,

each n is independently 0 to 5 inclusive;

each α is independently 0, 1, or 2;

each m is independently 0, 2, 3, 4, or 5;

Y is CH₂, NR, O, SO, SO₂, or S;

B is pyrrolyl, substituted pyrrolyl, imidazolyl, substituted imidazolyl,oxazolyl, substituted oxazolyl, thiazolyl, substituted thiazolyl,

—NR¹—(CH₂)_(n)—(CHX³)—(CH₂)_(n)—SR¹, —S—(CH₂)_(n)—(CHX³)—(CH₂)_(n)—SR¹,or

—(CH₂)_(n)—(CHX³)—(CH₂)_(n)—SR¹;

X¹ is S or NR¹;

X² is NR¹ or CH₂;

R¹ is hydrogen or C₁-C₆ alkyl;

X³ is hydrogen, —NR¹R¹, or —C₁-C₆ alkyl, and the pharmaceuticallyacceptable salts, esters, amides and prodrugs thereof

Also provided by the present invention are compounds having the FormulaIII

wherein Q is O, —NOR, or —N—NRR;

Z is hydrogen when - - - is absent and Z is —NRR, —R, —OR, —SR,—(CH₂)_(n)E, —O(CH₂)_(n)E, —NR(CH₂)_(n)E, —S(CH₂)_(n)E, —N¹-piperidinyl,—N¹-piperazinyl[N⁴—R], —N-pyrrolidinyl, —N-morpholino,—N-thiomorpholino, —N-hexahydroazepine, or an amino acid having thestructure

where A is a side chain of the amino acid glycine, alanine, valine,leucine, isoleucine, phenylalanine, proline, serine, threonine,tyrosine, asparagine, glutamine, lysine, arginine, tryptophan,histidine, cysteine, methionine, aspartic acid, or glutamic acid;

when - - - is a bond;

each R^(a) or R^(b) is independently hydrogen, C₁-C₆ alkyl, C₂-C₆alkenyl, phenyl, or substituted phenyl, or R^(a) and R^(b) along withthe carbon atom to which they are bonded form a C₃-C₆ cycloalkyl ring;

each R is independently hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, benzyl,C₂-C₆ alkenyl, phenyl, or substituted phenyl;

Each - - - is a bond or absent;

E is hydrogen, halogen, —CO₂R, —CONRR, —CN, —NO₂, C₁-C₆ perfluoroalkyl,C₁-C₆ perfluoroalkoxy, acetyl, —OR, —SR, —NRR, —N¹-piperidinyl, —N¹-piperazinyl[N⁴—R], —N-pyrrolidinyl, —N-morpholino, —N-thiomorpholino,—N-hexahydroazepine, aryl, heteroaryl, substituted aryl, or substitutedheteroaryl;

E′ is hydrogen, halogen, —NO₂, —NRR, —R, —OR, —S(O)_(α)R, —S(CH₂)_(n)E,—(CH₂)_(n)E, —O—(CH₂)_(n)E, —NR(CH₂)_(n)E, —CO₂R, —CONRR,

each n is independently 0 to 5 inclusive;

each α is independently 0, 1, or 2;

each m is independently 0, 2, 3, 4, or 5;

Y is CH₂, NR, O, or S;

A′ is aryl, heteroaryl, substituted aryl or substituted heteroaryl,C₃-C₆ cycloalkyl or C₃-C₆ substituted cycloalkyl, provided that anysubstituents are not —NO₂;

B is pyrrolyl, substituted pyrrolyl, imidazolyl, substituted imidazolyl,oxazolyl, substituted oxazolyl, thiazolyl, substituted thiazolyl,

—NR¹—(CH₂)_(n)—(CHX³)—(CH₂)_(n)—SR¹,

—S(CH₂)_(n)—(CHX³)—(CH₂)_(n)—SR¹, or

—(CH₂)_(n)—(CHX³)—(CH₂)_(n)—SR¹;

X¹ x is S or NR¹;

X² is NR¹ or CH₂;

R¹ is hydrogen or C₁-C₆ alkyl;

X³ is hydrogen, —NR¹R¹ or —C₁-C₆ alkyl, and the pharmaceuticallyacceptable salts, esters, amides, and prodrugs thereof.

The present invention also provides compounds having the Formula IV

wherein

each J is independently C₁-C₆ alkyl;

Y is CH₂, NR, O, SO, SO₂, or S;

each m is independently 0, 2, 3, 4, or 5;

each R^(a) or R^(b) is independently hydrogen, C₁-C₆ alkyl, C₂-C₆alkenyl, phenyl, substituted phenyl, or R^(a) and R^(b) together withthe carbon atom to which they are bonded form a C₃-C₆ cycloalkyl ring;

B is pyrrolyl, substituted pyrrolyl, imidazolyl, substituted imidazolyl,oxazolyl, substituted oxazolyl, thiazolyl, substituted thiazolyl,

—NR¹—(CH₂)_(n)—(CHX³)—(CH₂)_(n)—SR¹,

—S—(CH₂)_(n)—(CHX³)—(CH₂)_(n)—SR¹, or

—(CH₂)_(n)—(CHX³)—(CH₂)_(n)—SR¹;

X¹ is S or NR¹;

X² is NR¹ or CH₂;

R¹ is hydrogen or C₁-C₆ alkyl;

X³ is hydrogen —NR¹R¹ or —C₁-C₆ alkyl;

X is CH₂ or —O—;

Q is O, —NOR, —N—NRR, —NOCH₂CO₂R^(a),

each R is independently hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, benzyl,C₂-C₆ alkenyl, phenyl, or substituted phenyl;

each E′ is independently hydrogen, halogen, —NO₂, —NRR, —R, —OR,—S(O)_(α)R,

each a is independently 0, 1, or 2;

each n is independently 0 to 5;

E is hydrogen, halogen, —CO₂R, —CONRR, —CN, —NO₂, C₁-C₆ perfluoroalkyl,C₁-C₆ perfluoroalkoxy, acetyl, —OR, —SR, —NRR, —N¹-piperidinyl,—N¹-piperazinyl[N⁴—R], —N-pyrrolidinyl, —N-morpholino,—N-thiomorpholino, —N-hexahydroazepine, aryl, heteroaryl, substitutedaryl, or substituted heteroaryl;

and the pharmaceutically acceptable, salts, esters, amides, and prodrugsthereof.

It is noted that the symbol - - - represents a bond or is absent.

In Formulas I and III, the symbol - - - is intended to signify a doublebond either in the ring containing Q or exo to the ring. Preferably, thedouble bond is either exo to the ring or in the ring, but not both.

The term “alkyl” means a straight or branched hydrocarbon having from 1to 6 carbon atoms and includes, for example, methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl,and the like. The alkyl group can also be substituted with one or moreof the substituents listed below for aryl.

The term “cycloalkyl” means a saturated hydrocarbon ring which containsfrom 3 to 7 carbon atoms, for example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, adamantyl, and the like.

The term “aryl” means an aromatic ring which is a phenyl, 5-fluorenyl,1-naphthyl, or 2-naphthyl group, unsubstituted or substituted by 1 to 3substituents selected from alkyl, O-alkyl and S-alkyl, OH, SH, F, —CN,Cl, Br, I, CF₃, NO₂, NH₂, NHCH₃, N(CH₃)₂, NHCO-alkyl, (CH₂)_(m)CO₂H,(CH₂)_(m)CO₂-alkyl,

—NH alkyl, —N(alkyl)₂, —(CH₂)_(m)PO₃H₂, (CH₂)_(m)PO₃(alkyl)₂,(CH₂)_(m-k) SO₂NH₂, and (CH₂)_(m)SO₂NH-alkyl wherein alkyl is defined asabove and m is 0, 1, 2, or 3.

The term “heteroaryl” means an aromatic ring containing one or moreheteroatoms. Examples of heteroaryl radicals include thienyl, furanyl,pyrrolyl, pyridyl, imidazoyl, or indolyl group, substituted orunsubstituted by 1 or 2 substituents from the group of substituentsdescribed above for aryl. Examples of heteroatoms include nitrogen,oxygen, sulfur, and phosphorus.

The symbol “-” means a bond.

The term “patient” means all animals including humans. Examples ofpatients include humans, cows, dogs, cats, goats, sheep, and pigs.

A “therapeutically effective amount” is an amount of a compound of thepresent invention that when administered to a patient ameliorates asymptom of restenosis, cancer, or atherosclerosis or preventsrestenosis. A therapeutically effective amount of a compound of thepresent invention can be easily determined by one skilled in the art byadministering a quantity of a compound to a patient and observing theresult. In addition, those skilled in the art are familiar withidentifying patients having cancer, restenosis, or atherosclerosis orwho are at risk of having restenosis.

The term “cancer” includes, but is not limited to, the followingcancers:

breast;

ovary;

cervix;

prostate,

testis;

esophagus;

glioblastoma;

neuroblastoma;

stomach;

skin, keratoacanthoma;

lung, epidermoid carcinoma, large cell carcinoma, adenocarcinoma;

bone;

colon, adenocarcinoma, adenoma;

pancreas, adenocarcinoma;

thyroid, follicular carcinoma, undifferentiated carcinoma, papillarycarcinoma;

seminoma;

melanoma;

sarcoma;

bladder carcinoma;

liver carcinoma and biliary passages;

kidney carcinoma;

myeloid disorders;

lymphoid disorders, Hodgkins, hairy cells;

buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx;

small intestine;

colon-rectum, large intestine, rectum;

brain and central nervous system; and leukemia.

The term “pharmaceutically acceptable salts, esters, amides, andprodrugs” as used herein refers to those carboxylate salts, amino acidaddition salts, esters, amides, and prodrugs of the compounds of thepresent invention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of patients without unduetoxicity, irritation, allergic response, and the like, commensurate witha reasonable benefit/risk ratio, and effective for their intended use,as well as the zwitterionic forms, where possible, of the compounds ofthe invention. The term “salts” refers to the relatively non-toxic,inorganic and organic acid addition salts of compounds of the presentinvention. These salts can be prepared in situ during the finalisolation and purification of the compounds or by separately reactingthe purified compound in its free base form with a suitable organic orinorganic acid and isolating the salt thus formed. Representative saltsinclude the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate,acetate, oxalate, valerate, oleate, palmitate, stearate, laurate,borate, benzoate, lactate, phosphate, tosylate, citrate, maleate,fumarate, succinate, tartrate, naphthylate-mesylate, glucoheptonate,lactobionate and laurylsulphonate salts, and the like. These may includecations based on the alkali and alkaline earth metals, such as sodium,lithium, potassium, calcium, magnesium and the like, as well asnon-toxic ammonium, quaternary ammonium, and amine cations including,but not limited to ammonium, tetramethylammonium, tetraethylammonium,methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine,and the like. (See, for example, Berge S. M. et al., “PharmaceuticalSalts,” J. Pharm. Sci., 1977;66:1-19 which is incorporated herein byreference.) Examples of pharmaceutically acceptable, non-toxic esters ofthe compounds of this invention include C₁-C₆ alkyl esters wherein thealkyl group is a straight or branched chain. Acceptable esters alsoinclude C₅-C₇ cycloalkyl esters as well as arylalkyl esters such as, butnot limited to benzyl. C₁-C₄ alkyl esters are preferred. Esters of thecompounds of the present invention may be prepared according toconventional methods.

Examples of pharmaceutically acceptable, non-toxic amides of thecompounds of this invention include amides derived from ammonia, primaryC₁-C₆ alkyl amines and secondary C₁-C₆ dialkyl amines wherein the alkylgroups are straight or branched chain. In the case of secondary aminesthe amine may also be in the form of a 5- or 6-membered heterocyclecontaining one nitrogen atom. Amides derived from ammonia, C₁-C₃ alkylprimary amines and C₁-C₂ dialkyl secondary amines are preferred. Amidesof the compounds of the invention may be prepared according toconventional methods.

The term “prodrug” refers to compounds that are rapidly transformed invivo to yield the parent compound of the above formulae, for example, byhydrolysis in blood. A thorough discussion is provided in T. Higuchi andV Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S.Symposium Series, and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987, both of which are hereby incorporated by reference.

The compounds of the present invention can be administered to a patientalone or as part of a composition that contains other components such asexcipients, diluents, and carriers, all of which are well-known in theart. The compositions can be administered to humans and animals eitherorally, rectally, parenterally (intravenously, intramuscularly, orsubcutaneously), intracisternally, intravaginally, intraperitoneally,intravesically, locally (powders, ointments, or drops), or as a buccalor nasal spray.

Compositions suitable for parenteral injection may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propyleneglycol,polyethyleneglycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil), and injectable organic esters suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the action ofmicroorganisms can be ensured by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. It may also be desirable to include isotonic agents, forexample sugars, sodium chloride, and the like. Prolonged absorption ofthe injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monostearate andgelatin.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is admixed with at least one inert customary excipient (orcarrier) such as sodium citrate or dicalcium phosphate or (a) fillers orextenders, as for example, starches, lactose, sucrose, glucose,mannitol, and silicic acid; (b) binders, as for example,carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone,sucrose, and acacia; (c) humectants, as for example, glycerol; (d)disintegrating agents, as for example, agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, certain complex silicates, andsodium carbonate; (e) solution retarders, as for example paraffin; (f)absorption accelerators, as for example, quaternary ammonium compounds;(g) wetting agents, as for example, cetyl alcohol and glycerolmonostearate; (h) adsorbents, as for example, kaolin and bentonite; and(i) lubricants, as for example, talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, or mixturesthereof In the case of capsules, tablets, and pills, the dosage formsmay also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethyleneglycols, andthe like.

Solid dosage forms such as tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells, such as entericcoatings and others well-known in the art. They may contain opacifyingagents, and can also be of such composition that they release the activecompound or compounds in a certain part of the intestinal tract in adelayed manner. Examples of embedding compositions which can be used arepolymeric substances and waxes. The active compounds can also be inmicro-encapsulated form, if appropriate, with one or more of theabove-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art, such as water or othersolvents, solubilizing agents and emulsifiers, as for example, ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol,dimethylformamide, oils, in particular, cottonseed oil, groundnut oil,corn germ oil, olive oil, castor oil and sesame oil, glycerol,tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters ofsorbitan or mixtures of these substances, and the like.

Besides such inert diluents, the composition can also include adjuvants,such as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like.

Compositions for rectal administrations are preferably suppositorieswhich can be prepared by mixing the compounds of the present inventionwith suitable non-irritating excipients or carriers such as cocoabutter, polyethyleneglycol, or a suppository wax, which are solid atordinary temperatures but liquid at body temperature and therefore, meltin the rectum or vaginal cavity and release the active component.

Dosage forms for topical administration of a compound of this inventioninclude ointments, powders, sprays, and inhalants. The active componentis admixed under sterile conditions with a physiologically acceptablecarrier and any preservatives, buffers, or propellants as may berequired. Ophthalmic formulations, eye ointments, powders, and solutionsare also contemplated as being within the scope of this invention.

The compounds of the present invention can be administered to a patientat dosage levels in the range of about 0.1 to about 2,000 mg per day.For a normal human adult having a body weight of about 70 kilograms, adosage in the range of about 0.01 to about 100 mg per kilogram of bodyweight per day is preferable. The specific dosage used, however, canvary. For example, the dosage can depended on a numbers of factorsincluding the requirements of the patient, the severity of the conditionbeing treated, and the pharmacological activity of the compound beingused. The determination of optimum dosages for a particular patient iswell known to those skilled in the art.

The compounds of the present invention can exist in differentstereoisomeric forms by virtue of the presence of asymmetric centers inthe compounds. It is contemplated that all stereoisomeric forms of thecompounds as well as mixtures thereof, including racemic mixtures, formpart of this invention.

In addition, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms for the purposesof the present invention.

The examples presented below are intended to illustrate particularembodiments of the invention, and are not intended to limit the scope ofthe specification or the claims in any way.

PFT Inhibitory Activity

The protein:farnesyl transferase (PFT) or farnesyl protein transferase(FPT) inhibitory activity of compounds of the present invention wereassayed in HEPES buffer (pH 7.4) containing 5 mM potassium phosphate and20 μM ZnCl₂. The solution also contained 5 mM DTT (dithiothreitol), 5 mMMgCl₂, and 0.1% PEG 8000. Assays were performed in 96 well plates(Wallec) and employed solutions composed of varying concentrations of acompound of the present invention in 10% DMSO (dimethylsulfoxide). Uponaddition of both substrates, radiolabeled farnesyl pyrophosphate ([1³H],specific activity 15-30 Ci/mmol, final concentration 134 nM) and(biotinyl)-Ahe-Thr-Lys-Cys-Val-Ile-Met ([3aS[3a alpha, 4 beta, 6aalpha]-hexahydro-2-oxo-1H-thieno[3,4-d]imidazole-5-pentanoicacid]-[7-aminoheptanoic acid]-Thr-Lys-Cys-Val-Ile-Met) (Ahe is7-aminoheptanoic acid, Thr is threonine, Lys is lysine, Cys is cysteine,Val is valine, Ile is isoleucine, and Met is methionine) (finalconcentration 0.2 μM), the enzyme reaction was started by addition ofSF9 affinity purified rat FPT. After incubation at 30° C. for 30minutes, the reaction was terminated by diluting the reaction 2.5-foldwith a stop buffer containing 1.5 M magnesium acetate, 0.2 M H₃PO₄, 0.5%BSA (bovine serum albumin), and strepavidin beads (Amersham) at aconcentration of 1.3 mg/mL. After allowing the plate to settle for 30minutes at room temperature, radioactivity was quantitated on amicrobeta counter (Model 1450, Wallec). The assay was also carried outwithout 5 mM potassium phosphate.

The compounds of Formula I through IV may be prepared according to thesynthetic strategies described below in Schemes 1 through 5.

As exemplified for tetralones of Formula I, imidazole derivatives can beprepared by alkylation of the phenol with a dihaloalkane or similaralkane bearing two leaving groups followed by reaction with anappropriate nucleophile such as sodium imidazolide.

Alternatively, as shown in Scheme 2, hydroxyalkylimidazoles can becoupled to the phenol under Mitsunobu conditions employing, for example,diethylazodicarboxylate and triphenylphosphine. Direct alkylation of thephenol with haloalkylimidazoles can also be employed.

To obtain unsaturated compounds of Formula I, a ketone may be reactedwith aldehydes under a variety of aldol conditions, for example KOH inEtOH, piperidine in acetic acid, or sulfuric acid in acetic acid.

The ketones can be alkylated to provide for the saturated compounds ofFormula I according to Scheme 3. For example, enamines may be preparedby reaction with pyrrolidine under dehydrating conditions and subsequentalkylation with an alkyl halide. Alternatively, chiral or achiralhydrazides can be prepared by reaction of the ketone with achiralhydrazines (1,1-dimethyl-hydrazine, for example) or chiral hydrazines((S) or (R)-1-amino-2-(methoxymethyl)pyrrolidine, for example) underdehydrating conditions and subsequent deprotonation with a strong basesuch as lithium diisopropyl amide (LDA) followed by an alkylating agent.Hydrolysis of the hydrazones can be achieved with aqueous acid orcleavage can be achieved with ozone treatment, as appropriate, accordingto known art.

As an alternative to alkylation, reduction of the aldol products withhydrogen and an appropriate (chiral or achiral) catalyst or a hydridereagent such as potassium tri-sec-butylborohydride provide methods ofobtaining the saturated analogs according to Scheme 4.

The following abbreviations are used in the application.

HPLC High pressure liquid chromatography

CI-MS Chemical Ionization Mass Spectrometry

mp Melting point

rt Room temperature

TBF Tetrahydrofuran

APCI-MS Atmospheric pressure chemical ionization mass spectrometry

dec Decomposes

AcCN Acetonitrile

HOAc Acetic acid

CHCl₃ Chloroform

DCM Dichloromethane

DMF N,N′-Dimethylformamide

EtOAc Ethyl acetate

EtOH Ethanol

Et₂O Diethyl ether

HCl Hydrochloric acid

H₂O₂ Hydrogen peroxide

H₂SO₄ Sulfuric acid

KOH Potassium hydroxide

MeCN Acetonitrile

MeOH Methanol

NaH Sodium hydride

NaOH Sodium hydroxide

NaHCO₃ Sodium bicarbonate

iPrOH iso-Propanol

TFA Trifluoroacetic acid

Boc tertiary Butyloxycarbonyl

Ts Tosylate

Ph₃P Triphenylphosphine

Melting points are uncorrected. Proton N (¹H-NMR) spectra were obtainedat 400 MHz and are reported relative to tetramethylsilane (TMS). Whenindicated, analytical HPLC was performed on Vydac C18 peptide/proteincolumns eluting with gradients of water/acetonitrile containing 0.1%TFA. Flash chromatography was performed using Merck or ICN silica gel,60A, 230-400 mesh. THF was distilled from Na/benzophenone and all othersolvents were reagent grade and dried over 4A molecular sieves unlessotherwise indicated.

EXAMPLE 1 6-(2-Imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-oneStep 1: 6-(β-Chloroethoxy)-1-tetralone

To a solution of 6-hydroxy tetralone (2.0 g, 12.3 mmol) in DMF (50 mL)was added dry cesium carbonate (8.02 g, 24.6 mmol). Neat2-chloroethyl-p-toluensulfonate (3.49 g, 14.9 mmol) was added to thismixture and the reaction stirred at room temperature for 58 hours. Thereaction was poured into 200 mL of water and to this mixture was added10 mL of 1N NaOH followed by 200 mL of Et₂O. The mixture stirred at roomtemperature for 2 hours. The aqueous portion was separated and extractedwith Et₂O (3×200 mL). The combined organic portions were washedsuccessively with 1N NaOH (2×100 mL), water (2×100 mL), and brine,dried, filtered, and concentrated under vacuum to give 5.07 g of afaintly orange solid. The solid was dissolved in minimal DCM andchromatographed (silica gel, 190 g, DCM). The appropriate fractions werepooled and concentrated under vacuum to afford 2.65 g (96%) of a whitecrystalline solid:

¹H-NMR (CDCl₃): δ7.97 (1H, d, J=8.8 Hz), 6.79 (1H, dd, J=8.8 Hz, J=2.4Hz), 6.69 (1H, br s), 4.26-4.23 (2H, m), 3.80-3.78 (2H, m), 2.88 (2H, t,J=6 Hz), 2.57 (2H, t, J=6 Hz), 2.11-2.05 (2H, m).

Step 2: 6-(2-Imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one

A suspension of NaH (0.29 g, 7.2 mmol, 60% oil dispersion prewashed withdry hexanes) in 18 mL of dry DMF under a nitrogen flow was cooled to 0°C. and imidazole (0.49 g, 7.2 mmol) was added portionwise. The ice bathwas removed and the reaction stirred at room temperature 20 minutes. Thereaction was cooled to 0° C. and a solution of6-(β-chloroethoxy)-1-tetralone (1.07 g, 4.8 mmol) in 12 mL of dry DMFwas added over several minutes. The ice bath was removed and thereaction stirred at room temperature overnight. The reaction waspartitioned between 20 mL of water and 200 mL of EtOAc. The organicportion was removed, and the aqueous portion was extracted with EtOAc(5×50 mL). The combined extracts were washed successively with water andbrine, dried, filtered, and concentrated under vacuum to afford 1.6 g ofcrude product. Purification by flash chromatography (silica gel, 130 g,8% MeOH in DCM) afforded 0.83 g (67%) of an off-white crystalline solid:CI-MS m/e 256 (M⁺), 257 (M⁺+1);

¹H-NMR (CDCl₃): δ7.96 (1H, dd, J=8.5 Hz, J=3.0 Hz), 7.61 (1H, s), 7.05(1H, s), 7.00 (1H, s), 6.75 (1H, dd, J=8.8 Hz, J=3.0 Hz), 6.63 (1H, d,J=3.0 Hz), 4.34 (2K m), 4.23 (2H, m), 2.87 (2H, t, J=6.0 Hz), 2.57 (2H,t, J=6.0 Hz), 2.07 (2H, m).

EXAMPLE 26-[2-(2-Methyl-imidazole-1-yl)-ethoxy]-3,4-dihydro-2H-naphthalen-1-one

According to the method of Example 1, Step 2,6-(β-chloroethoxy)-1-tetralone (0.208 g, 0.93 mmol) and2-methylimidazole (0.137 g, 1.67 mmol) were reacted to provide the titlecompound (0.166 g, 66%) as a cream colored solid: CI-MS m/e 270 (M⁺),271 (M⁺+1);

¹H-NMR (CDCl₃): δ7.94 (1H, d, J=8.0 Hz), 6.88 (2H, s), 6.72 (1H, dd,J=8.0 Hz, J=2.0 Hz), 6.60 (1H, d, J=2 Hz), 4.21 (4H, m), 2.85 (2H, t,J=6.0 Hz), 2.55 (2H, t, 3=6.0 Hz), 2.41 (3H, s), 2.05 (2H, m).

EXAMPLE 36-(2-Imidazole-1-yl-ethoxy)-2-pyridin-2-ylmethylene-3,4-dihydro-2H-naphthalen-1-one

2-Pyridine carboxaldehyde (0.202 g, 1.9 mmol) was added to a mixture of6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (1) (0.322g, 1.2 mmol) in piperidine:acetic acid (30 μL:24 μL). The reactionmixture was heated in a 130° C. oil bath with efficient stirring for 1.5hours. After cooling to room temperature, 2 mL of 1N HCl was added andthe mixture stirred overnight. The mixture was made neutral with theaddition of a saturated solution of NaHCO₃ and then extracted into DCM(3×50 mL). The pooled extracts were washed sequentially several timeswith water, then brine, dried, filtered, and concentrated in vacuo toleave a dark brown oil. Purification by flash chromatography (silicagel, 135 g, 7% MeOH in DCM) afforded 0.075 g of the title compound as alight tan solid.

EXAMPLE 46-(2-Imidazole-1-yl-ethoxy-2-(4-methylsulfanyl-benzylidene)-3,4-dihydro-2H-naphthalen-1-one

4-(Methylthio)benzaldehyde (0.114 g, 0.75 mmol) was added to a stirringsolution of (1) (0.25 g, 0.98 mmol) in 2 mL 4% KOH in EtOH (wt/vol). Thereaction stirred at room temperature for 2 hours and the resultingprecipitate was collected and washed well with water and then coldiPrOH. The solid was dried in vacuo at 40° C. for 3 hours affording thetitle compound, 0.277 g (95%) as an off-white solid, mp 161-161.5° C.;CI-MS m/e 390 (M⁺), 391 M⁺+1);

¹H-NMR (CDCl₃): δ8.06 (1H, d, J=8.6 Hz), 7.75 (1H, s), 7.56 (1H, s),7.33 (2H, d, J=8.3 Hz, Ph), 7.23 (2H, d, J=8.3 Hz, Ph), 7.05 (1H, s),7.00 (1H, s), 6.81 (1H, dd, J=8.6 Hz, J=2.5 Hz) 6.64 (1H, d, J=2.5 Hz),4.34 (2H, m), 4.25 (2H, m), 3.06 (2H, m), 2.86 (2H, m), 2.48 (3H, s).Elemental Analysis (C₂₃H₂₂S₁N₂O₂): Calculated: C, 70.74; H, 5.68; N,7.17. Found: C, 70.36; H, 5.64; N, 7.11.

EXAMPLE 52-(4-Bromo-benzylidene)-6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one

According to the method of Example 4,6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.40 g, 1.6mmol) was reacted with 4-bromobenzaldehyde (0.433 g, 2.3 mmol) in 2 mLof 4% KOH in ethanol to afford 0.543 g (81%) of the title compound as acoarse white solid, mp 152-153° C.: CI-MS m/e 423, 425 (M⁺);

¹H-NMR (CDCl₃): δ8.06 (1H, d, J=8.5 Hz), 7.70 (1H, s), 7.56 (1H, s),7.50 (2H, d, J=8.3 Hz, Ph), 7.24 (2H, d, J=8.3 Hz, Ph), 7.05 (1H, s),7.00 (1H, s), 6.81 (1H, dd, J=2.4 Hz, J=8.5 Hz), 6.64 (1H, d, J=2.4 Hz),4.34 (2H, m), 4.25 (2H, m), 3.02 (2H, m), 2.86 (2H, m). ElementalAnalysis (C₂₂H₁₉N₂O₂Br)×0.22 H₂O: Calculated: C, 61.84; H, 4.59; N,6.56. Found: C, 61.85; H, 4.53; N, 6.51.

EXAMPLE 66-(2-Imidazole-1-yl-ethoxy)-2-pyridin-4-ylmethylene-3,4-dihydro-2H-naphthalen-1-one

6-(2-Imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.50 g,1.95 mmol) was reacted with 4-pyridinecarboxaldehyde (0.248 g, 2.3 mmol)in 2.5 mL of 4% KOH for 8 hours at room temperature. The reaction wasdiluted with water, the resulting mixture was filtered, and the filtratewas extracted into EtOAc. The combined extracts were evaporated todryness, and the resulting yellow solid was purified twice by flashchromatography (silica gel, 120 g, 9% MeOH in DCM) to afford 0.146 g ofa yellow oil which crystallized on standing. Recrystallization fromminimal iPrOH afforded the title compound as a light yellow powder(0.041 g, 6%), mp 128.5-129° C., CI-MS m/e 345 (M⁺), 346 M⁺+1);

¹H-NMR (CDCl₃): δ8.62 (2H, d, J=6.1 Hz), 8.08 (1H, d, J=8.5 Hz), 7.66(1H, s), 7.56 (1H, s), 7.24 (2H, d, J=6.1 Hz), 7.05 (1H, s), 7.00 (1H,s), 6.83 (1H, dd J=2.5 Hz, J=8.5 Hz), 6.65 (1H, d, J=2.5 Hz), 4.34 (2H,m), 4.26 (2H, m), 3.02 (2H, m), 2.88 (2H, m). Elemental Analysis(C₂₁H₁₉N₃O₂): Calculated: C, 72.11; H, 5.30; N, 12.02. Found: C, 71.95;H, 5.08; N, 11.91.

EXAMPLE 76-(2-Imidazole-1-yl-ethoxy)-2-(4-nitro-benzylidene)-3,4-dihydro-2H-naphthalen-1-one

According to the method of Example 4,6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.19 g,0.74 mmol) was reacted with 4-nitrobenzaldehyde (0.112 g, 0.74 mmol) in1.5 mL of 4% KOH in ethanol for 3 hours at room temperature to afford0.195 g (68%) of the title compound as a fine tan powder, mp 184-185°C.: CI-MS m/e 389 (M⁺), 390 M⁺+1);

¹H-NMR (CDCl₃): δ8.23 (2H, d, J=8.8 Hz, Ph), 8.08 (1H, d, J=8.8 Hz),7.79 (1H, s), 7.78 (1H, s), 7.51 (2 d, J=8.8 Hz, Ph), 7.08 (1H, s), 7.04(1H, s), 6.83 (1H, dd, J=8.8 Hz, J=2.4 Hz), 6.66 (1H, d, J=2.4 Hz), 4.39(2H, m), 4.28 (2H, m), 3.03 (2H, m), 2.89 (2H, m). Elemental Analysis(C₂₂H₁₉N₃O₄): Calculated: C, 67.86; H, 4.92; N, 10.79. Found: C, 67.33;H, 4.60; N, 10.43.

EXAMPLE 82-[4-(2-Diethylamino-ethoxy)-benzylidene]-6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one

6-(2-Imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.505 g,1.97 mmol) was reacted with 4-(diethylamino)ethoxy benzaldehyde (0.662g, 3.0 mmol) in 2.5 mL of 4% KOH for 20 hours at room temperature. Thereaction was diluted with brine, and the resulting mixture was extractedinto DCM. The combined extracts were dried, filtered, and evaporated todryness. The resulting oil was purified twice by flash chromatography(silica gel, 150 g, 10% MeOH in DCM) to afford 0.274 g (30%) of thetitle compound as a yellow oil: CI-MS m/e 459 (M⁺), 460 M⁺+1);

¹H-NMR (CDCl₃): δ8.05 (1H, d, J=8.7 Hz), 7.76 (1H, s), 7.56 (1H, s),7.35 (2H, d, J=8.6 Hz, Ph), 7.04 (1H, s), 7.00 (1H, s), 6.90 (2H, d,J=8.6 Hz, Ph), 6.80 (1H, dd, J=8.7 Hz, J=2.4 Hz), 6.64 (1H, d, J=2.4Hz), 4.33 (2H, t, J=6.1 Hz), 4.25 (2H, t, J=6.1 Hz), 4.06 (2H, t, J=6.4Hz), 3.07 (2H, m), 2.88-2.83 (4H, m), 2.61 (4H, q, J=7.1 Hz), 1.05 (6H,t, J=7.1 Hz). Elemental Analysis (C₂₈H₃₃N₃O₃)×1.0 H₂O: Calculated: C,70.41; H, 7.39; N, 8.80. Found: C, 70.54; H, 7.05; N, 8.61.

EXAMPLE 92-Benzylidene-6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one

According to the method of Example 8,6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.505 g,1.97 mmol) was reacted with benzaldehyde (0.312 g, 2.94 mmol) in 3.0 mLof 4% KOH in EtOH overnight at room temperature to afford 0.596 g (88%)of the title compound as a cream-colored solid: CI-MS m/e 344 (M⁺), 345M⁺+1);

¹H-NMR (CDCl₃): δ8.07 (1H, d, J=8.7 Hz), 7.80 (1H, s), 7.56 (1H, s),7,39-7.31 (5H, m), 7.04 (1H, s), 7.00 (1H, s), 6.81 (1H, br d, J=8.7Hz), 6.64 (1H, br s), 4.33 (2H, t, J=4.9 Hz), 4.25 (2H, t, J=4.9 Hz),3.07 (2H, t, J=6 Hz), 2.86 (2H, t, J=6 Hz). Elemental Analysis(C₂₂H₂₀N₂O₂): Calculated: C, 76.72; H, 5.85; N, 8.13. Found: C, 70.54;H, 6.01; N, 7.95.

EXAMPLE 106-(2-Imidazole-1yl-ethoxy)-2-(4-methylsulfanyl-benzyl)-3,4-dihydro-2H-naphthalen-1-one

Potassium tri-sec-butylborohydride, 1.0 M in THF (0.64 mL) was added toa solution of Compound (4) (0.250 g, 0.64 mmol) in 4.0 mL of dry THF at−78° C. under a nitrogen atmosphere. After 2 hours, the cooling bath wasreplaced with an ice bath and the reaction warmed to 0° C. at which time10% NaOH (7.0 mL) and 30% H₂O₂ (5.0 mL) were added. The ice bath waspermitted to melt. The reaction was diluted with water and extractedinto DCM. The pooled organics were washed with water and brine, dried,filtered, and concentrated under vacuum. The resulting oil was purifiedby flash chromatography (silica gel, 56 g, 8% MeOH in DCM) to afford0.100 g of a faintly yellow solid. Recrystallization of the solid fromiPrOH afforded 0.026 g (10%) of the title compound as granular,cream-colored crystals, mp 114-117° C.: CI-MS m/e 392 (M⁺), 393 M⁺+1);

¹H-NMR (CDCl₃): δ7.99 (1H, d, J=8.4 Hz), 7.55 (1H, br s), 7.13 (4H, ABq, J=8.1 Hz, J=24.2 Hz), 7.04 (1H, br s), 6.99 (1H, br s), 6.76 (1H, brd, J=8.4 Hz), 6.59 (1H, br s), 4.32 (2H, m), 4.21 (2H, m), 3.38 (1H, brm), 2.65-2.53 (2H, m), 2.43 (3H, s), 2.04-2.00 (1H, m), 1.82-1.65 (1H,br m). Elemental Analysis (C₂₃H₂₄N₂SO₂)×0.24 H₂O×0.08 iPrOH: Calculated:C, 69.50; H, 6.30; N, 6.97. Found: C, 69.50; H, 6.15; N, 6.66.

EXAMPLE 116-(2-Imidazole-1yl-ethoxy)-2-thiophen-3-ylmethylene-3,4-dihydro-2H-naphthalen-1-one

According to the method of Example 8,6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.250 g,0.98 mmol) was reacted with 3-thiophene carboxaldehyde (0.166 g, 1.48mmol) in 5.0 mL of 4% KOH in EtOH at room temperature to afford 0.265 g(77%) of the title compound as a cream-colored solid, mp 61-62° C.:CI-MS m/e 350 (M⁺), 351 M⁺+1);

¹H-NMR (CDCl₃): δ8.04 (1H, d, J=8.6 Hz), 7.77 (1H, s), 7.56 (1H, s),7.45 (1H, m), 7.33 (1H, m), 7.24 (1H, m), 7.04 (1H, s), 7.00 (1H, s),7.80 (1H, dd J=8.6 Hz, J=2.4 Hz), 6.64 (1H, d, J=2.4 Hz), 4.33 (2H, m),4.24 (2H, m), 3.10 (2H, m), 2.89 (2H, m). Elemental Analysis(C₂₀H₁₈N₂SO₂)×0.5 H₂O: Calculated: C, 66.83; H, 5.33; N, 7.80. Found: C,67.04; H, 4.94; N, 7.56.

EXAMPLE 124-[6-(2-Imidazole-1-yl-ethoxy)-1-oxo-3,4-dihydro-1H-naphthalen-2-ylidenemethyl]-benzoicacid

6-(2-Imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.400 g,1.56 mmol) was reacted with 4-formyl benzoic acid (0.351 g, 2.34 mmol)in 5.0 mL of 4% KOH in EtOH and 1 mL of dioxane at room temperature for6 days. The reaction was diluted with minimal water to achieve completesolution and then extracted with DCM. The resulting aqueous solution wasacidified to pH 2 with 1N HCl. After standing at room temperature for 3weeks, 0.061 g (10%) of the title compound was isolated by filtration asa fine cream powder, mp 267-267.5° C.: CI-MS m/e 388 (M⁺), 389 M⁺+1);

¹H-NMR (CDCl₃): δ7.94 (2H, d, J=8.3 Hz, Ph), 7.87 (1H, d, J=8.5 Hz),7.64 (1H, br s), 7.62 (1H, br s), 7.56 (2H, d, J=8.3 Hz, Ph), 7.20 (1H,br s), 6.91 (1H, dd, J=2.4 Hz, J=8.5 Hz), 6.87 (1H, d, J=2.4 Hz), 6.84(1H, s), 4.34-4.30 (4H, m), 3.00 (2H, m), 2.85 (2H, m). ElementalAnalysis (C₂₀H₁₈N₂SO₂)×0.25 H₂O: Calculated: C, 70.31; H, 5.26; N, 7.13.Found: C, 70.14; H, 5.01; N, 6.91.

EXAMPLE 132-(4-Bromo-benzyl)-6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one

To a mixture of dry sodium iodide (0.146 g, 0.97 mmol) and Compound 5(0.200 g, 0.47 mmol) in AcCN 2.0 mL of dry at room temperature was addedtetra-chlorosilane (0.11 mL, 0.97 mmol). After stirring for 5 hours atroom temperature, the reaction was diluted with water and extracted intoCHCl₃. The pooled extracts were decolorized by washing with a 10%solution of sodium thiosulfate. The resulting solution was washed withwater, dried, filtered, and concentrated to afford 0.230 g of crudeproduct which contained the title compound and its enolized tautomer (asobserved by ¹H-NMR). Purification by flash chromatography (silica gel,40 g, 8% MeOH in DCM) afforded 0.066 g (33%) of the title compound as adark peach solid, mp 129-130.5° C.: CI-MS m/e 424/426 (M⁺),425/427M⁺+1).

Elemental Analysis (C₂₂H₂₁N₂BrO₂): Calculated: C, 62.13; H, 4.98; N,6.59. Found: C, 61.87; H, 4.71; N, 6.39.

EXAMPLE 146-(2-Imidazole-1-yl-ethoxy)-2-thiophen-2-ylmethylene-3,4-dihydro-2H-naphthalen-1-one

According to the method of Example 8,6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.400 g,1.56 mmol) was reacted with 2-thiophene carboxaldehyde (0.264 g, 2.35mmol) in 5.0 mL of 4% KOH in EtOH for 4.5 hours at room temperature toafford 0.369 g (67%) of the title compound as dark yellow crystals, mp137-138° C.: CI-MS m/e 350 (M⁺), 351 M⁺+1);

¹H-NMR (CDCl₃): δ8.04 (1H, d, J=8.6 Hz), 7.98 (1H, s), 7.59 (1H, s),7.47 (1H, d, J=4.9 Hz), 7.34 (1H, d, J=3.4 Hz), 7.10 (1H, m), 7.05 (1H,s), 7.01 (1H, s), 6.80 (1H, dd, J=8.6 Hz, J=2.4 Hz), 6.67 (1H, br s),4.34 (2H, m), 4.25 (2H, m), 3.15 (2H, m), 2.94 (2H, m). ElementalAnalysis (C₂₀H₁₈N₂SO₂)×0.17 H₂O: Calculated: C, 67.95; H, 5.23; N, 7.93.Found: C, 67.95; H, 5.28; N, 7.77.

EXAMPLE 156-(2-Imidazole-1-yl-ethoxy)-2-naphthalen-1-ylmethylene-3,4-dihydro-2H-naphthalen-1-one

According to the method of Example 6,6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.475 g,1.85 mmol) was reacted with 1-naphthaldehyde (0.448 g, 2.87 mmol) in 3.0mL of 4% KOH in EtOH for 6 hours at room temperature to afford 0.639 g(88%) of the title compound as a bright yellow solid, mp 147-148° C.:CI-MS m/e 494 (M⁺), 495 M⁺+1);

¹H-NMR (CDCl₃): δ8.30 (1H, s), 8.14 (1H, d, J=8.5 Hz), 7.98-7.95 (1H,m), 7.87-7.82 (2H, m), 7.58 (1H, br s), 7.50-7.44 (3H, m), 7.37 (1H, m),7.05 (1H, s), 7.01 (1H, s), 6.84 (1H, dd, J=8.5 Hz, J=2.2 Hz), 6.64 (1H,s), 4.34 (2H, m), 4.26 (2H, m), 2.92 (2H, m), 2.83 (2H, m). ElementalAnalysis (C₂₆H₂₂N₂O₂)×0.64 H₂O: Calculated: C, 76.92; H, 5.78; N, 6.90.Found: C, 76.92; H, 5.51; N, 6.75.

EXAMPLE 162-Furan-2-ylmethylene-6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one

According to the method of Example 6,6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.250 g,0.98 mmol) was reacted with 2-furaldehyde (0.151 g, 1.57 mmol) in 3.0 mLof 4% KOH in EtOH for 15 hours at room temperature to afford 0.220 g(67%) of the title compound as a light tan solid, mp 109-110° C.: CI-MSm/e 334 (M⁺), 335 M⁺+1);

¹H-NMR (CDCl₃): δ8.03 (1H, d, J=8.8 Hz), 7.57 (1H, s), 7.51 (2H, s),7.04 (1H, s), 7.00 (1H, s), 6.80 (1H, dd, J=8.8 Hz, J=2.5 Hz), 6.68-6.64(2H, m), 6.47 (1H, m), 4.33 (2H, m), 4.24 (2H, m), 3.27 (2H, m), 2.91(2H, m). Elemental Analysis (C₂₀H₁₈N₂O₃)×0.2 H₂O: Calculated: C, 71.07;H, 5.49; N, 8.29. Found: C, 71.13; H, 5.71; N, 8.13.

EXAMPLE 172-(4-Bromo-thiophen-2-ylmethylene)-6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one

According to the method of Example 4,6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.252 g,0.98 mmol) was reacted with 4-bromothiophene-2-carboxaldehyde (0.282 g,1.5 mmol) in 5 mL of 4% KOH in EtOH to afford 0.181 g (43%) of the titlecompound as a light tan powder, mp 164-166° C.: CI-MS m/e 428, 430 (M⁺);429, 431 M⁺+1);

¹H-NMR (CDCl₃): δ8.03 (1H, d, J=8.8 Hz), 7.82 (1H, s), 7.58 (1H, s),7.33 (1H, s), 7.20 (1H, s), 7.05 (1H, s), 7.01 (1H, s), 6.80 (1H, dd,J=8.8 Hz, J=2.4 Hz), 6.66 (1H, d, J=2.2 Hz), 4.34 (2H, m), 4.25 (2H, m),3.10 (2H, m), 2.93 (2H, m). Elemental Analysis (C₂₀H₁₇BrN₂SO₂)×0.61 H₂O:Calculated: C, 54.55; H, 4.17; N, 6.36. Found: C, 54.55; H, 4.07; N,6.34.

EXAMPLE 182-(5-Chloro-thiophen-2-ylmethylene)-6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one

According to the method of Example 4,6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.25 g,0.98 mmol) was reacted with 5-chlorothiophene-2-carboxaldehyde (0.215 g,1.47 mmol) in 5 mL of 4% KOH in EtOH to afford 0.293 g (77%) of thetitle compound as a coarse cream solid, mp 143-144° C.: APCI-MS m/e385.5 M⁺+1);

¹H-NMR (CDCl₃): δ8.03 (1H, d, J=8.5 Hz), 7.81 (1H, s), 7.65 (1H, s),7.10 (1H, d, J=3.9 Hz), 7.06 (1H, s), 7.02 (1H, s), 6.91 (1H, d, J=3.9Hz), 6.80 (1H, m), 3.05 (2H, m), 2.93 (2H, m). Elemental Analysis(C₂₀H₁₇ClN₂SO₂)×0.14 H₂O×0.02 iPrOH: Calculated: C, 62.00; H, 4.52; N,7.21. Found: C, 62.00; H, 4.19; N, 7.03.

EXAMPLE 196-(2-Imidazole-1-yl-ethoxy)-2-(5-methylsulfanyl-thiophen-2-ylmethylene)-3,4-dihydro-2H-naphthalen-1-one

According to the method of Example 4,6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.25 g,0.98 mmol) was reacted with 5-(methylthio)thiophene-2-carboxaldehyde(0.233 g, 1.47 mmol) in 4 mL of 4% KOH in EtOH for 2 hours at roomtemperature to afford 0.293 g (36%) of the title compound as a darkyellow powder, mp 102-104° C.: APCI-MS m/e 397.5 M⁺+1).

Elemental Analysis (C₂₁H₂₀N₂S₂O₂)×0.65 H₂O×0.12 EtOH: Calculated: C,61.66; H, 5.36; N, 6.77. Found: C, 61.66; H, 5.00; N, 6.71.

EXAMPLE 206-(2-Imidazole-1-yl-ethoxy)-2-(3-phenoxy-thiophen-2-ylmethylene)-3,4-dihydro-2H-naphthalen-1-one

According to the method of Example 4,6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.25 g,0.98 mmol) was reacted with 3-phenoxythiophene-2-carboxaldehyde (0.300g, 1.47 mmol) in 4 mL of 4% KOH in EtOH for 3 hours at room temperatureto afford 0.331 g (76%) of the title compound as an off-white solid, mp135-137° C.: APCI-MS m/e 443.5 M⁺+1).

Elemental Analysis (C₂₆H₂₂N₂SO₃)×0.21 H₂O: Calculated: C, 69.97; H,5.06; N, 6.28. Found: C, 69.96; H, 4.68; N, 6.03.

EXAMPLE 212-[2,2′]Bithiophenyl-5-ylmethylene-6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one

According to the method of Example 4,6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.200 g,0.78 mmol) was reacted with 2,2′-bisthiophene-5-carboxaldehyde (0.233 g,1.2 mmol) in 4 mL of 4% KOH in EtOH at room temperature overnight toafford 0.284 g (84%) of the title compound as a yellow solid, mp180-181° C.: APCI-MS mi/e 433.4 M⁺+1).

Elemental Analysis (C₂₄H₂₀N₂O₂S₂)×0.40 H₂O: Calculated: C, 65.55; H,4.77; N, 6.37. Found: C, 65.55; H, 4.65; N, 6.19.

EXAMPLE 226-(2-Imidazole-1-yl-ethoxy)-2-(5-nitro-thiophen-2-ylmethylene)-3,4-dihydro-2H-naphthalen-1-one

6-(2-Imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.200 g,0.78 mmol) was reacted with 5-nitrothiophene-2-carboxaldehyde (0.123 g,0.78 mmol) in a mixture of HOAc (1 mL) and concentrated H₂SO₄ (0.100 mL)at room temperature overnight. The reaction was diluted with water, andthe resulting precipitate was collected, washed well with water, anddried in vacuo at 60° C. to afford 0.296 g (80%) of the title compoundas a brown powder, mp >240° C.: APCI-MS m/e 396.1 M⁺+1).

Elemental Analysis (C₂₀H₁₇N₃SO₄)×1.39 H₂O×0.53 H₂SO₄: Calculated: C,50.84; H, 4.45; N, 8.89; S, 10.38. Found: C, 50.84; H, 4.39; N, 8.82; S,10.37.

EXAMPLE 232-Furan-3-ylmethylene-6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one

According to the method of Example 8,6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.20 g,0.78 mmol) was reacted with 3-furaldehyde (0.083 g, 0.86 mmol) in 2 mLof 4% KOH in EtOH for 48 hours at room temperature to afford 0.182 g(70%) of the title compound, mp 116-117° C.: APCI-MS m/e 335.3 M⁺+1).

Analysis Calculated for (C₂₀H₁₈N₂O₃)×0.27 H₂O: C, 70.81; H, 5.51; N,8.26. Found: C, 70.78; H, 5.42; N, 8.14.

EXAMPLE 246-(2-Imidazole-1-yl-ethoxy)-2-(4-methoxy-benzylidene)-3,4-dihydro-2H-naphthalen-1-one

According to the method of Example 4,6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.200 g,0.78 mmol) was reacted with p-anisaldehyde (0.117 g, 0.87 mmol) in 2 mLof 4% KOH in EtOH at room temperature overnight to afford 0.248 g (84%)of the title compound, mp 132-133° C.: APCI-MS m/e 375 M⁺+1).

Elemental Analysis (C₂₃H₂₂N₂O₃)×0.18 H₂O: Calculated: C, 73.14; H, 5.97;N, 7.42. Found: C, 73.14; H, 5.88; N, 7.30.

EXAMPLE 256-(2-Imidazol-1-yl-ethoxy)-2-(2-methoxy-benzylidene)-3,4-dihydro-2H-naphthalen-1-one

6-(2-Imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.200 g,0.78 mmol) was reacted with o-anisaldehyde (0.117 g, 0.87 mmol) in 2 mLof 4% KOH in EtOH at room temperature overnight. The reaction wasdiluted with water to induce the precipitation of a red gum. The aqueouslayer was decanted, and the remaining residue was concentrated severaltimes from EtOH and then chromatographed (SiO₂, 30 g, 8% MeOH in DCM) toafford 0.249 g (84%) of the title compound as a yellow foam: APCI-MS m/e375.3 M⁺+1).

Elemental Analysis (C₂₃H₂₂N₂O₃)×0.47 H₂O. Calculated: C, 72.15; H, 6.04;N, 7.32. Found: C, 72.16; H, 5.77; N, 7.17.

EXAMPLE 266-(2-Imidazole-1-yl-ethoxy)-2-thiazol-2-ylmethylene-3,4-dihydro-2H-naphthalen-1-oneStep 1:2-(Hydroxy-thiazol-2-yl-methyl)-6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one

6-(2-Imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.200 g,0.78 mmol) was reacted with 2-formylthiazole (0.107 g, 0.94 mmol) in amixture of HOAc (1 mL) and concentrated H₂SO₄ (0.100 mL) at roomtemperature overnight. The resulting biphasic reaction mixture wasdiluted with water and then extracted with EtOAc. The aqueous portionwas made to pH 10 with 50% NaOH and extracted with EtOAc (3×50 mL). Thepooled organic extracts were washed well with water, dried, filtered,and concentrated to afford 0.215 g (74%) of the title compound as agolden oil: APCI-MS m/e 370.2 M⁺+1).

Step 2:6-(2-Imidazole-1-yl-ethoxy)-2-thiazol-2-ylmethylene-3,4-dihydro-2H-naphthalen-1-one

Conversion of the product from Step 1 to the title compound is achievedby treatment with trifluoroacetic anhydride.

EXAMPLE 276-[2-(1H-Imidazole4-yl)-ethoxy]-3,4-dihydro-2H-naphthalen-1-one,monohydrochloride

6-Hydroxytetralone (1.46 g, 9.01 mmol) was dissolved in a mixture of 15mL AcCN and 8 mL DMF, and solid potassium carbonate (4.98 g, 36 mmol)was added followed by a solution of 4-(2-bromoethyl)-1H-imidazolehydrobromide (2.05 g, 8.01 mmol) in a mixture of 15 mL AcCN and 3 mLDMF. After stirring for 24 hours at room temperature, the reaction wasconcentrated in vacuo to remove the solvents, and the resulting residuewas diluted with water and extracted into EtOAc. The pooled organicswere washed sequentially with a saturated solution of NaHCO₃, water, andbrine and concentrated in vacuo to afford 1.57 g of crude product.Purification by flash chromatography (silica gel, 235 g, 5% MeOH in DCM)gave a yellow oil. The oil was taken up in 7 mL DCM, and the product wasprecipitated as a salt by the addition of 1.5 mL of 8N HCl in iPrOH. Thesolid was collected, washed with iPrOH, triterated with Et₂O, and driedin vacuo to afford 0.826 g (33%) of the title compound;

¹H-NMR (DMSO-d₆): δ8.97 (1H, d, J=1 Hz), 7.75 (1H, m), 7.46 (1H, d, J=1Hz), 6.85 (2H, m), 4.28 (2H, m), 3.08 (2H, m), 2.84 (2H, m), 2.46 (2H,m), 1.94 (2H, m). Elemental Analysis (C₁₅H₁₆N₂O₂)×1.0 HCl×1.22 H₂O:Calculated: C, 57.31; H, 6.23; N, 8.91; Cl, 11.16. Found: C, 57.27; H,6.14; N, 8.88; Cl, 11.41.

EXAMPLE 286-[2-(1H-Imidazole-4-yl)-ethoxy]-2-thiophen-3-ylmethylene-3,4-dihydro-2H-naphthalen-1-one

According to the method of Example 32, Step 2,4-[2-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethyl]-imidazole-1-carboxylicacid tert-butyl ester (0.270 g, 0.76 mmol) was reacted withthiophene-3-carboxaldehyde (0.128 g, 1.14 mmol) in 5 mL of 4% KOH inEtOH for 22 hours to afford, after chromatography (silica gel, 50 g; 8%MeOH in DCM), 0.167 g (59%) of the title compound as a dull yellowpowder, mp 94-96° C.: CI-MS m/e 351 (M⁺+1).

Elemental Analysis (C₂₀H₁₈N₂SO₂)×0.29 DCM×0.21 H₂O: Calculated: C,64.33; H, 5.06; N, 7.39. Found: C, 64.41; H, 5.09; N, 7.11.

EXAMPLE 296-[2-(1H-Imidazole-4-yl)-ethoxy]-2-thiophen-2-ylmethylene-3,4-dihydro-2H-naphthalen-1-one

According to the method of Example 32, Step 2,4-[2-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethyl]-imidazole-1-carboxylicacid tert-butyl ester (0.356,g, 1.0 mmol) was reacted withthiophene-2-carboxaldehyde (0.174 g, 1.55 mmol) in 5 mL of 4% KOH inEtOH for 24 hours to afford, after chromatography (silica gel, 60 g; 8%MeOH in DCM), 0.154 g (40%) of the title compound as a red glassy solid,mp 60-63° C.: CI-MS m/e 351 (M⁺+1).

Elemental Analysis (C₂₀H₁₈N₂SO₂)×0.45 DCM×0.06 H₂O: Calculated: C,63.02; H, 4.92; N, 7.19. Found: C, 63.01; H, 4.91; N, 7.03.

EXAMPLE 302-Benzylidene-6-[2-(1H-imidazole-4-yl)-ethoxy]-3,4-dihydro-2H-naphthalen-1-oneStep 1:4-[2-(5-Oxo-5,6.7.8-tetrahydro-naphthalen-2-yloxy)-ethyl]-imidazole-1-carboxylicacid tert-butyl ester

A solution of 1-N-Boc-4-(2-hydroxyethyl)imidazole (1.06 g, 5.0 mmol),6-hydroxytetralone (0.811 g, 5.0 mmol), and triphenylphosphine (1.44 g,5.5 mmol) in 10 mL of freshly distilled THF was cooled in an ice bathfor 10 minutes and then treated with neat diethyl azodicarboxylate (0.87mL, 5.5 mmol) added via syringe through a rubber septum. The ice bathwas permitted to melt and the reaction continued at room temperature for5 hours. The solvent was removed in vacuo and the residue waschromatographed (silica gel, 500 g; 1:1, EtOAc:hexanes), and the purefractions were pooled to afford 0.61 g (33%) of the title compound as aclear, colorless, viscous oil: CI-MS m/e 357 (M⁺+1).

Step 2:2-Benzylidene-6-[2-(1H-imidazole-4-yl)-ethoxy]-3,4-dihydro-2H-naphthalen-1-one

According to the method of Example 6, the product of Step 1 (0.271 g,0.76 mmol) was reacted with benzaldehyde (0.121 g, 1.14 mmol) in 5 mL of4% KOH in EtOH for 3 hours at room temperature to afford 0.125 g (46%)of the title compound as a foam which solidified on standing to give ayellow solid, mp 53-56° C.: CI-MS m/e 345 (M⁺+1).

Elemental Analysis (C₂₀H₂₄N₂O₂)×0.13 DCM: Calculated: C, 74.78; H, 5.75;N, 7.88. Found: C, 74.92; H, 5.62; N, 7.72.

EXAMPLE 316-[2-(1H-Imidazole-4-yl)-ethoxy]-2-(4-methylsulfanyl-benzylidene)-3,4-dihydro-2H-naphthalen-1-one

6-[2-(1H-Imidazole-4-yl)-ethoxy]-3,4-dihydro-2H-naphthalen-1-one (29)(0.18 g, 0.70 mmol) was dissolved in 5 mL of 4% KOH in EtOH (wt/vol) andtreated with 4-(methylthio)benzaldehyde (0.172 g, 1.13 mmol). Afterstirring for 22 hours at room temperature, the reaction was diluted withwater and extracted into EtOAc. The pooled organics were washedsequentially with water and brine, dried, filtered, and concentrated invacuo to afford 0.39 g of crude product. Purification by flashchromatography (silica gel, 60 g, 8% MeOH in DCM) afforded 0.174 g (64%)of a bright yellow foam which solidified, mp 65-70° C.: CI-MS m/e 390(M⁺), 391 (M⁺+1).

Elemental Analysis (C₂₃H₂₂N₂O₂S)×0.10 DCM: Calculated: C, 69.54; H.5.61; N, 7.02. Found: C, 69.65; H, 5.42; N, 7.00.

EXAMPLE 326-[2-(1H-Imidazole-4-yl)-ethoxy]-2-(5-methylsulfanyl-thiophen-2-ylmethylene)-3,4-dihydro-2H-naphthalen-1-one,monohydrochloride

According to the method of Example 33,6-[2-(1H-imidazole-4-yl)-ethoxy]-3,4-dihydro-2H-naphthalen- -one,monohydrochloride (0.313 g, 1.07 mmol) was reacted with(5-methylthio)thiophene-2-carboxaldehyde (0.178 g, 1.13 mmol) in 5 mL of4% KOH in EtOH overnight. After workup and purification, the productobtained from chromatography (silica gel, 10% MeOH in DCM) was taken upin minimal DCM and then precipitated upon the addition of 8N HCl iniPrOH. The solid was collected, washed with iPrOH, triterated with Et₂O,recrystallized from EtOH/Et₂O, and dried in vacuo to afford 0.262 g(52%), mp 168-169° C.: CI-MS m/e 397 (M⁺+1).

Elemental Analysis (C₂₁H₂₀N₂O₂S₂)×1.03 HCl×2.13 H₂O: Calculated: C,53.39; H, 5.40; N, 5.93; Cl, 7.73. Found: C, 53,43, H, 5.33; N, 5.81;Cl, 7.50.

EXAMPLE 334-{6-[2-(1H-Imidazole-4-yl)-ethoxy]-1-oxo-3,4-dihydro-1H-naphthalen-2-ylidenemethyl}-benzamide,monohydrochloride

According to the method of Example 34,6-[2-(1H-imidazole-4-yl)-ethoxy]-3,4-dihydro-2H-naphthalen-1-one,monohydrochloride (0.313 g, 1.07 mmol) was reacted withbenzamide-4-carboxaldehyde (0.178 g, 1.13 mmol) in 5 mL of 4% KOH inEtOH overnight to afford 0.197 (42%) of the title compound as anoff-white powder, mp dec. >230° C.: CI-MS m/e 388 (M⁺+1).

Elemental Analysis (C₂₃H₂₁N₃O₃)×1.06 HCl×0.72 H₂O: Calculated: C, 62.92;H, 5.39; N, 9.57; Cl, 8.56. Found: C, 63.01; H, 5.18; N, 9.47; Cl, 8.44.

EXAMPLE 34N,N-Diethyl-4-{6-[2-(1H-imidazole-4-yl)-ethoxy]-1-oxo-3,4-dihydro-1H-naphthalen-2-ylidenemethyl}-benzamide,monohydrochloride

According to the method of Example 34,6-[2-(1H-midazole-4-yl)-ethoxy]-3,4-dihydro-2H-naphthalen-1-one,monohydrochloride (0.313 g, 1.07 mmol) was reacted withN,N-diethylbenzamide-4-carboxaldehyde (0.231 g, 1.13 mmol) in 5 mL of 4%KOH in EtOH overnight to afford 0.277 (53%) of the title compound as alight yellow powder, mp 211-213° C.: CI-MS m/e 444 (M⁺+1).

Elemental Analysis (C₂₇H₂₉N₃O₃)×0.97 HCl×0.68 H₂O: Calculated: C, 66.03;H, 6.43; N, 8.56; Cl, 7.00. Found: C, 66.00; H, 6.33; N, 8.47; Cl, 6.98.

EXAMPLE 354-{6-[2-(1H-Imidazole-4-yl)-ethoxy]-1-oxo-3,4-dihydro-1H-naphthalen-2-ylidenemethyl}-benzoicacid, ditrifluoroacetate

According to the method of Example 34,6-[2-(1H-imidazole-4-yl)-ethoxy]-3,4-dihydro-2H-naphthalen-1-one,monohydrochloride (0.313 g, 1.07 mmol) was reacted with 4-formyl benzoicacid, ethyl ester (0.200 g, 1.12 mmol) in 5 mL of 4% KOH in EtOHovernight, and the resulting solid was purified by preparative HPLC(C18, 0.1% TFA in H₂O: 0.1% TFA in AcCN; gradient 80:20 to 20:80) toafford 0.237 g (35%) of the title compound as a cream-colored powder, mpdec. 202-204° C.: APCI-MS m/e 389 (M⁺+1).

EXAMPLE 362-(5-Chloro-thiophen-2-ylmethylene)-6-[2-(1H-imidazole-4-yl)-ethoxy]-3,4-dihydro-2H-naphthalen-1-one,hydrochloride

According to the method of Example 34,6-[2-(1H-imidazole-4-yl)-ethoxy]-3,4-dihydro-2H-naphthalen-1-one,monohydrochloride (0.313 g, 1.07 mmol) was reacted with5-chloro-2-thiophene carboxaldehyde (0.165 g, 1.13 mmol) in 5 mL of 4%KOH in EtOH overnight to afford 0.272 g (60%) of the title compound as adull yellow powder, mp dec. >210° C.: CI-MS m/e 385, 387 (M⁺—Cl).

Elemental Analysis (C₂₀H₁₇N₂CISO₂)×0.99 HCl×1.71 H₂O: Calculated: C,53.17; H, 4.78; N, 6.20; Cl, 7.77. Found: C, 53.03; H, 4.47; N, 6.13;Cl, 7.82.

EXAMPLE 376-[2-(1H-Imidazole-4-yl)-ethoxy]-2-(5-methyl-thiophen-2-ylmethylene)-3,4-dihydro-2H-naphthalen-1-one

According to the method of Example 34,6-[2-(1H-imidazole-4-yl)-ethoxy]-3,4-dihydro-2H-naphthalen-1-one,monohydrochloride (0.313 g, 1.07 mmol) was reacted with5-methyl-2-thiophene carboxaldehyde (0.142 g, 1.13 mmol) in 5 mL of 4%KOH in EtOH overnight to afford 0.207 g (44%) of the title compound as abright orange solid, mp 69-70° C.: CI-MS m/e 364 (M⁺), 365 (M⁺+1).

Elemental Analysis (C₂₁H₂₀N₂SO₂)×1.0 HCl×2.11 H₂O: Calculated: C, 57.46;H, 5.79; N, 6.38; Cl, 8.08. Found: C, 57.24; H, 5.50; N, 6.18; Cl, 7.95.

EXAMPLE 385-{6-[2-(1H-Imidazol-4-yl)-ethoxy]-1-oxo-3,4-dihydro-1H-naphthalen-2-ylidenemethyl}-thiophene-2-carboxylicacid

According to the method of Example 34,6-[2-(1H-imidazole-4-yl)-ethoxy]-3,4-dihydro-2H-naphthalen-1-one,monohydrochloride (0.220 g, 0.75 mmol) was reacted with5-carboxymethyl-2-thiophene carboxaldehyde (0.191 g, 1.12 mmol) in 5 mLof 4% KOH in EtOH overnight, and the resulting solid was purified bypreparative HPLC (C18, 0.1% TFA in H₂O:0.1% TFA in AcCN; gradient 80:20to 20:80) to afford 0.302 g (75%) of the title compound as a light tanpowder, mp dec. >200° C.: APCI-MS m/e 395 (M⁺+1).

Elemental Analysis (C₂₁H₁₈N₂SO₄)×1.0 TFA×1.46 H₂O: Calculated: C, 51.59;H, 4.12; N, 5.23; F, 10.74. Found: C, 51.80; H, 3.73; N, 5.26; F, 10.49.

EXAMPLE 396-[2-(1H-Imidazole-4-yl)-ethoxy]-2-(3-methyl-thiophen-2-ylmethylene)-3,4-dihydro-2H-naphthalen-1-one

According to the method of Example 4,6-[2-(1H-imidazole-4-yl)-ethoxy]-3,4-dihydro-2H-naphthalen-1-one,monohydrochloride (0.146 g, 0.50 mmol) was reacted with3-methyl-thiophene-2-carboxaldehyde (0.095 g, 0.50 mmol) in 5 mL of 4%KOH in EtOH to afford 0.115 g (63%) of the title compound as a coarsecream powder, mp 191-193° C.: CI-MS m/e 365 (M⁺).

EXAMPLE 406-[2-(1H-Imidazole-4-yl)-ethoxy]-2-(1-phenyl-ethylidene)-3,4-dihydro-2H-naphthalen-1-oneStep 1: 1,6-Bis-trimethylsilanyloxy-3,4-dihyrdo-naphthalene

To a solution of 6-hydroxytetralone (0.972 g, 6.0 mmol) in 10 mL offreshly distilled AcCN at room temperature was added sequentially dryNaI (2.25 g, 15 mmol), TEA (2.10 mL, 15 mmol), and chlorotrimethylsilane(1.92 mL, 15 mmol). After stirring for 1 hour, the reaction was quenchedwith the addition of a cold solution of saturated ammonium chloride andthe reaction was extracted into Et₂O (2×100 mL). The combined extractswere washed with ice cold water and then dried, filtered, andconcentrated in vacuo to afford 1.53 g of the title compound as acolorless oil which was used for further reaction without purification.

Step 2:6-Hydroxy-2-(1-phenyl-ethylidene)-3,4-dihydro-2H-naphthalen-1-one

Under a nitrogen atmosphere, a solution of the compound obtained fromStep 1 and SnCl₄ (0.70 mL, 6 mmol) in 4 mL dry DCM was prepared in FlaskA and stirred for 15 minutes at room temperature. Phenylacetylene (0.404g, 4 mmol) and Bu₃N (0.96 mL, 4 mmol) in dry AcCN was added to an AcCN(10 mL) solution of SnCl₄ (0.46 mL, 4.18 mmol) in Flask B, and themixture was stirred for 10 minutes at room temperature. The contents ofFlask A were transferred to Flask B. The reaction mixture was stirred atreflux for 1 hour and then poured over ice-cold saturated aqueous NH₄Cl.EtOAc was added, and the organic extract was separated and washed with0.5N HCl. The organic portion was then poured into 0.5N KOH and filteredto remove a fine precipitate. The organic portion was separated from thefiltrate, and the aqueous KOH portion was extracted with EtOAc. Thepooled organic extracts were washed with 0.5N HCl then water, dried,filtered, and concentrated to leave 0.410 g of crude product.Chromatography (SiO₂, 60 g, 20% EtOAc in hexanes) afforded 0.186 g (12%)of the title compound as a crystalline solid, CI-MS m/e 265 (M⁺+1).

Step 3:6-[2-(1H-Imidazole-4-yl)-ethoxy]-2-(1-phenyl-ethylidene)-3,4-dihydro-2H-naphthalen-1-one

The product obtained from Step 2 (0.180 g, 0.68 mmol) was dissolved in 5mL of dry DMF and treated with K₂CO₃ (0.376 g, 2.72 mmol) and4-(2-bromoethyl)imidazole hydrobromide (0.192 g, 0.75 mmol). Afterstirring overnight at room temperature, the reaction was diluted withwater and extracted with EtOAc. The pooled extracts were washed wellwith aqueous 0.5N KOH, water and brine, and then dried, filtered, andconcentrated. Purification of the residue (SiO₂, 5% MeOH in DCM)afforded 0.120 g (49%) of the title compound as a light yellow foam.Conversion of this product to its HCl salt according to the method ofExample 34 afforded 0.063 g of a light yellow powder, mp 170-172° C.:CI-MS m/e 359 (M⁺+1).

Elemental Analysis (C₂₃H₂₂N₂O₂)×0.25 H₂O×1.0 HCl: Calculated: C, 69.17;H. 5.93; N, 7.01. Found: C, 69.48; H, 6.03; N, 7.03.

EXAMPLE 412-Furan-2-ylmethylene-6-[2-(1H-imidazole-4-yl)-ethoxy]-3,4-dihydro-2H-naphthalen-1-one

According to the method of Example 32,4-[2-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethyl]-imidazole-1-carboxylicacid tert-butyl ester (0.270 g, 0.75 mmol) was reacted with2-furylaldehyde (0.095 mL, 1.14 mmol) in 5 mL of 4% KOH in EtOHovernight to afford 0.190 g (76%) of the title compound as a foam whichsolidified on standing to give a dark red powder, mp 57-60° C.: CI-MSm/e 335 (M⁺+1).

Elemental Analysis (C₂₀H₁₈N₂O₃)×0.13 DCM: Calculated: C, 70.00; H, 5.33;N, 8.11. Found: C, 69.91; H, 5.27; N, 8.01.

EXAMPLE 422-(4-Bromo-benzylidene)-6-[2-(1H-imidazole-4-yl)-ethoxy]-3,4-dihydro-2H-naphthalen-1-one

According to the method of Example 32,4-[2-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethyl]-imidazole-1-carboxylicacid tert-butyl ester (0.278 g, 0.78 mmol) was reacted withp-bromobenzaldehyde (0.217 g, 1.17 mmol) in 5 mL of 4% KOH in EtOHovernight to afford 0.173 g (51%) of the title compound as a darkcream-colored powder, mp 176-178° C.: CI-MS m/e 423, 425 M⁺+1).

Elemental Analysis (C₂₂H₁₉N₂O₂)×0.16 DCM: Calculated: C, 60.92; H,L4.46; N, 6.41. Found: C, 60.89; H, 4.33; N, 6.31.

EXAMPLE 436-[3-(1H-Imidazole-4-yl)-propoxy]-3,4-dihydro-2H-naphthalen-1-one,hydrochloride Step 1:6-[3-(1-Trityl-1H-imidazole-4-yl)-propoxy]-3,4-dihydro-2H-naphthalen-1-one

According to the method of Example 32, Step 1,3-[1-(triphenylmethyl)-1H-imidazole-4-yl]propanol (see for example, J.Med. Chem., 1996;39: 1220-1226) (2.58 g, 7 mmol) was coupled to6-hydroxy tetralone (1.30 g, 7 mmol) with diethylazodicarboxylate (1.26mL, 8 mmol) and triphenylphosphine (2.10 g, 8 mmol) in 10 mL of dry THFto afford, after chromatography (SiO₂, 50% EtOAc in hexanes), 2.73 g ofa 1:1 mixture of the title compound and Ph₃PO as determined by HPLCanalysis (C18, 0.1% TFA in H₂O:0.1% TFA in AcCN gradient 80:20 to20:80): title compound, retention time=15.87 minutes (48.2%); Ph₃PO,retention time=13.12 minutes (50.1%). CI-MS m/e 279 (Ph₃PO), 513 (M⁺+1).

Step 2:6-[3-(1H-Imidazole-4-yl)-propoxy]-3,4-dihydro-2H-naphthalen-1-one,hydrochloride

The product obtained from Step 1 (1.20 g) was heated under reflux in amixture of 10 mL EtOH and 2N HCl (20 mL) for 1 hour, cooled to roomtemperature, and evaporated to dryness in vacuo. The residue wassuspended in water and the mixture stirred for 1 hour, filtered, and thefiltrate was evaporated several times from EtOH. The resulting solid wasrecrystallized from EtOH/water to afford 0.576 g of the title compound,mp 153-155° C.: CI-MS m/e 271 (M⁺+1).

Elemental Analysis (C₁₆H₁₈N₂O₂)×1.0 HCl×1.0 H₂O.

EXAMPLE 44(E,E)-6-(2-Imidazol-1-yl-ethoxy)-2-(3-phenyl-allylidene)-3,4-dihydro-2H-naphthalen-1-one

A solution of 0.2 g (0.8 mmol) of6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone in 2 mLof 4% KOH in EtOH was treated with 0.1 mL (0.8 mmol) of cinnamaldehydeand stirred at room temperature overnight. The mixture was diluted withH₂O and the solid collected. Recrystallization from MeOH/H₂O gave 197 mg(68.2% yield) of the pure product as a yellow solid, mp 198-200° C. Thestructure was confirmed by NMR and mass spectroscopy. MS m/z 371 (m+H⁺).

Calculated for C₂₄H₂₂N₂O₂×0.2 H₂O (MW 374.04): C, 77.06; H, 6.04; N,7.49. Found: C, 76.81; H, 5.82; N, 7.42.

EXAMPLE 452-[(E)-1-Cyclohexylmethylidene]-6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone,hydrochloride

A solution of 0.2 g (0.8 mmol) of6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone in 2 mLof 4% KOH in EtOH was treated with 0.1 mL (0.8 mmol) ofcyclohexylaldehyde and the solution allowed to stir at room temperaturefor 3 days. The solution was diluted with CH₂Cl₂ and the layersseparated. The CH₂Cl₂ was washed with saturated NaCl and dried overMgSO₄. The CH₂Cl₂ was treated with HCl gas and the solvent removed. Theresidue was taken up in H₂O and freeze-dried. There was obtained 35 mg(10% yield) of a hygroscopic solid. The structure was confirmed by massspectroscopy. MS m/z 351 (m+H⁺).

EXAMPLE 466-[2-(1H-1-Imidazolyl)ethoxy]-7-methyl-2-[(E)-1-(2-thienyl)methylidene]-1,2,3,4-tetrahydro-1-naphthalenoneStep 1: 3-Methoxy-4-methylbenzyl bromide

A solution of 18.3 g (0.12 mol) of 3-methoxy-4-methylbenzyl alcohol in150 mL of Et₂O was treated with 23.8 g (0.12 mol) of BaCO₃ and themixture cooled in ice. This was treated dropwise with 5.8 mL (0.06 mol)of PBr₃. After stirring at 0° C. for 15 minutes, the mixture was allowedto stir at room temperature overnight. The mixture was filtered and thesolid washed with Et₂O. The Et₂O was washed with saturated NaHCO₃, thenwith saturated NaCl. Drying over MgSO₄ and removal of the solvent underreduced pressure left 24.17 g (93.5% yield) of the product as an oil.The structure was confirmed by NMR spectroscopy. Step 2: Dimethyl2-(3-methoxy-4-methylbenzyl)malonate

A solution of 2.6 g (0.1124 g-atom) of Na in 50 mL of MeOH was treatedwith 12.9 mL (0.1124 mol) of dimethyl malonate and allowed to stir for45 minutes. This was then treated dropwise with 24.17 g (0.1124 mol) of3-methoxy-4-methylbenzyl bromide and the solution heated at refluxovernight. The solvent was removed under reduced pressure and theresidue taken up in EtOAc. This was washed with 6% HCl, H₂O, saturatedNaHCO₃, and saturated NaCl. Drying over MgSO₄ and removal of the solventunder reduced pressure gave 28.54 g (95.5% yield) of the product as apale yellow oil. The structure was confirmed by NMR spectroscopy.

Step 3: 3-(3-Methoxy-4-methylphenyl)propanoic acid

A solution of 25.84 g (0.1072 mol) of dimethyl2-(3-methoxy-4-methylbenzyl)malonate in 150 mL of MeOH was treated witha solution of 20 g (0.5 mol) of NaOH in 100 mL of H₂O and heated atreflux overnight. The solution was concentrated under reduced pressureand the residue taken up in H₂O and washed with Et₂O. The solution wasacidified to Congo Red end point with dilute HCl and the solutionextracted with Et₂O. The Et₂O was washed with saturated NaCl and driedover MgSO₄. Removal of the solvent under reduced pressure gave 25.6 g ofan oil. This was taken up in 125 mL of dioxane and heated at refluxovernight. Removal of the solvent under reduced pressure gave 20.5 g ofthe crude product. Chromatography on silica gel, eluting with CHCl₃/MeOH(98/2) gave 8.65 g (41.6% yield) of the product as a white solid, mp80-82° C. The structure was confirmed by NMR and mass spectroscopy. MSm/z 195 (M+H⁺).

Step 4: 3-(3-Methoxy-4-methylphenyl)-1-propanol

A suspension of 3.3 g (98.1 mmol) of lithium aluminum hydride in 40 mLTHF was treated dropwise with a solution of 8.65 g (44.5 mmol) of3-(3-methoxy-4-methylphenyl)propanoic acid in 125 mL of THF. Afterstirring at room temperature for 0.5 hour, the mixture was heated atreflux for 2 hours. The mixture was cautiously acidified with 1N H₂SO₄,then extracted with EtOAc. The EtOAc was washed with 1N H₂SO₄, H₂O,saturated NaHCO₃, and saturated NaCl. Drying over MgSO₄ and removal ofthe solvent under reduced pressure left 7.33 g (91.6% yield) of theproduct as a clear oil. The structure was confirmed by NMR and massspectroscopy. MS m/z 181 (M+H⁺).

Step 5: 4-(3-Bromopropyl)-2-methoxy-1-methylbenzene

Under N₂, a solution of 7.33 g (40.7 mmol) of3-(3-methoxy-4-methylphenyl)-1-propanol in 200 mL of CH₂Cl₂ was treatedwith 10.67 g (40.7 mmol) of triphenylphosphine followed in portions by7.3 g (40.7 mmol) of recrystallized N-bromosuccinimide. The solution wasstirred at room temperature for 2 hours, then filtered through flashsilica gel. Removal of the solvent under reduced pressure left 8.68 g(87.9% yield) of the product as a clear oil. The structure was confirmedby NMR spectroscopy.

Step 6: 3-(3-Methoxy-4-methylphenyl)propyl cyanide

A solution of 8.68 g (35.7 mmol) of4-(3-bromopropyl)-2-methoxy-1-methylbenzene in 50 mL of acetone and 50mL of EtOH was treated with a solution of 2.8 g (42.8 mmol) of KCN in 20mL of H₂O and heated at reflux overnight. The solvent was removed underreduced pressure and the residue taken up in EtOAc and washed with H₂O,then saturated NaCl. Drying over MgSO₄ and removal of the solvent underreduced pressure left 6.75 g (100% yield) of the product as an oil. Thestructure was confirmed by NMR and IR spectroscopy.

Step 7: 4-(3-Methoxy-4-methylphenyl)butanoic acid

A solution of 6.75 g (35.7 mmol) of 3-(3-methoxy-4-methylphenyl)propylcyanide in 75 mL of EtOH was treated with a solution of 8.0 g (0.2 mol)of NaOH in 40 mL of H₂O and heated at reflux overnight. The solvent wasremoved under reduced pressure and the residue taken up in H₂O. Afterwashing with Et₂O, the aqueous solution was acidified to the Congo Redend point with dilute HCl. A white solid separated which was collectedand dried. There was obtained 5.6 g (75.5% yield) of the product, mp69-70° C. The structure was confirmed by NMR and mass spectroscopy. MSm/z 209 (M+H⁺).

Step 8: 6-Methoxy-7-methyl-1,2,3,4-tetrahydro-1-naphthalenone

A solution of 5.6 g (26.9 mmol) of 4-(3-methoxy-4-methylphenyl)butanoicacid in 100 mL of CH₂Cl₂ was cooled in ice and treated dropwise with 25mL of trifluoroacetic anhydride. After stirring at 0° C. for 1 hour, thesolution was diluted with Et₂O and washed twice with 5% NaOH, then withsaturated NaCl. Drying over MgSO₄ and removal of the solvent underreduced pressure left the crude product. Chromatography on silica gel,eluting with CH₂Cl₂ gave 2.79 g (54.7% yield) of the product as a whitesolid, mp 104-107° C. The structure was confirmed by NMR and massspectroscopy. MS m/z 191 (M+H⁺).

Step 9: 6-Hydroxy-7-methyl-1.2,3,4-tetrahydro-1-naphthalenone

A solution of 2.79 g (14.7 mmol) of6-methoxy-7-methyl-1,2,3,4-tetrahydro-1-naphthalenone in 150 mL ofCH₂Cl₂ was cooled in ice and treated with 20 mL (0.22 mol) of BBr₃.After stirring at 0° C. for 0.5 hour, the solution was stirred at roomtemperature overnight. The solution was poured into ice water andextracted with Et₂O. The Et₂O was extracted twice with 5% NaOH and theNaOH washed with Et₂O. The NaOH solution was acidified to the Congo Redend point with dilute HCl, then extracted with Et₂O. The Et₂O was washedwith saturated NaCl and dried over MgSO₄. Removal of the solvent underreduced pressure left the crude product. This was taken up in acetoneand treated with charcoal. Filtering through Celite and removal of thesolvent under reduced pressure left 2.08 g (80.6% yield) of the productas a brown solid. The structure was confirmed by NMR and massspectroscopy. MS m/z 177 (M+H⁺).

Step 10:6-[2-(1H-1-Imidazolyl)ethoxy]-7-methyl-1,2,3,4-tetrahydro-1-naphthalenone

Under N₂, a solution of 2.08 g (11.8 mmol) of6-hydroxy-7-methyl-1,2,3,4-tetrahydro-1-naphthalenone in 25 mL of THFwas treated with 1.46 g (13.9 mmol) of 2-(1H-1-imidazolyl)-1-ethanol and3.1 g (11.8 mmol) of triphenylphosphine. The solution was cooled in iceand treated with a solution of 1.9 mL (11.8 mmol) of diethylazodicarboxylate in 5 mL of THF. The solution was allowed to stir atroom temperature overnight. The mixture was diluted with EtOAc andwashed twice with H₂O, twice with saturated NaHCO₃, then with saturatedNaCl. Drying over MgSO₄ and removal of the solvent under pressure leftthe crude product. Chromatography on silica gel, eluting with CHCl₃/MeOH(95/5) gave the product which was recrystallized from EtOAc/hexane togive 1.05 g (32.9% yield) of the product as a tan solid, mp 118-120° C.The structure was confirmed by NMR and mass spectroscopy. MS m/z 271(M+H⁺).

Step 11:6-[2-(1H-1-Imidazolyl)ethoxy]-7-methyl-2-[(E)-1-(2-thienyl)methylidene]-1,2,3,4-tetrahydro-1-naphthalenone

A solution of 0.2 g (0.7 mmol) of6-[2-(1H-1-imidazolyl)ethoxy]-7-methyl-1,2,3,4-tetrahydro-1-naphthalenonein 2 mL of 4% KOH in EtOH was treated with 0.1 mL (0.7 mmol) of2-thiophene-aldehyde and let stirring at room temperature overnight. Themixture was diluted with H₂O and the solid collected. Recrystallizationfrom MeOH/H₂O gave 165 mg (61.3% yield) of the product as a yellowsolid, mp 150-151° C. The structure was confirmed by NMR and massspectroscopy. MS m/z 365 (M+H⁺).

Calculated for C₂₁H₂₀N₂O₂×0.4 H₂O (MW 371.59): C, 67.87; H, 5.64; N,7.54. Found: C, 67.82; H, 5.48; N, 7.51.

EXAMPLE 476-[2-(1H-1-Imidazolyl)ethoxy]-5-methyl-1,2,3,4-tetrahydro-1-naphthalenoneStep 1: 3-Hydroxy-2-methylbenzoic acid

A solution of 20.6 g (0.125 mol) of methyl 3-amino-2-methylbenzoate in150 mL of HOAc and 25 mL of conc. H₂SO₄ was cooled in ice and diazotizedby the dropwise addition of a solution of 8.7 g (0.125 mol) of NaNO₂ in50 mL of H₂O. After stirring for 15 minutes, the diazonium solution wasadded dropwise to a boiling solution of 200 mL of 50% H₂SO₄, and therefluxing continued for 15 minutes after the addition was complete. Themixture was diluted with H₂O and extracted twice with Et₂O. The Et₂O waswashed 5 times with H₂O, then with saturated NaCl. Drying over MgSO₄ andremoval of the solvent under reduced pressure left 17.98 g (94.4% yield)of the product as a tan solid, mp 137-140° C. The structure wasconfirmed by NMR spectroscopy.

Step 2: Methyl 3-hydroxy-2-methylbenzoate

A solution of 17.98 g (0.118 mol) of 3-hydroxy-2-methylbenzoic acid in200 L of MeOH was treated with 2.0 mL of conc. H₂SO₄ and heated atreflux overnight. The solution was concentrated under reduced pressureand diluted with H₂O. The product was collected and recrystallized fromMeOH/H₂O to give 12.85 g (65.6% yield) of a tan solid, mp 74-75° C. Thestructure was confirmed by NMR and mass spectroscopy. MS m/z 167 (M+H⁺).

Step 3: Methyl 3-methoxy-2-methylbenzoate

A solution of 13.98 g (0.0841 mol) of methyl 3-hydroxy-2-methylbenzoatein 120 mL of DMF was cooled in ice and treated dropwise with 200 mL (0.1mol) of a 0.5 M solution of KHMDS in toluene. After stirring for 10minutes, 7.8 mL (0.126 mol) of methyl iodide was added and the solutionallowed to stir at room temperature overnight. The solution was dilutedwith EtOAc and washed twice with 6% HCl, 3 times with H₂O, 10% NaHSO₃,then saturated NaCl. Drying over MgSO₄ and removal of the solvent underreduced pressure left 14.22 g (93.8% yield) of the product as a goldenoil. The structure was confirmed by NMR and mass spectroscopy. MS m/z181 (M+H⁺).

Step 4: (3-Methoxy-2-methylphenyl)methanol

A suspension of 4.5 g (0.118 mol) of lithium aluminum hydride in 100 mLof THF was treated dropwise with a solution of 14.22 g (78.9 mmol) ofmethyl 3-methoxy-2-methylbenzoate in 120 mL of THF. The mixture washeated at reflux for 2.5 hours, then cautiously decomposed with 1NH₂SO₄.The mixture was extracted with EtOAc, and the EtOAc washed with diluteHCl, H₂O, saturated NaHCO₃, and saturated NaCl. Drying over MgSO₄ andremoval of the solvent under reduced pressure left 11.5 g (95.8% yield)of the product as a tan solid, mp 63-64° C. The structure was confirmedby NMR and mass spectroscopy MS n/z 153 (M+H⁺).

Step 5: 1-(Bromomethyl)-3-methoxy-2-methylbenzene

Following the procedure of Example 46, Step 1, but using 11.5 g (75.6mmol) of(3-methoxy-2-methylphenyl)methanol, there was obtained 15.96 g(98.3% yield) of the product as a golden oil. The structure wasconfirmed by spectroscopy.

Step 6: Dimethyl 2-(3-methoxy-2-methylbenzyl)malonate

Following the procedure of Example 46, Step 2, but using 15.96 g (72.4mmol) of 1-(bromomethyl)-3-methoxy-2-methylbenzene, there was obtained19.0 g (96.2% yield) of the product as an oil that crystallized onstanding. The structure was confirmed by NMR and mass spectroscopy. MSm/z 267 (M+H⁺).

Step 7: 3-(3-Methoxy-2-methylphenyl)propanoic acid

Following the procedure of Example 46, Step 3, but using 19.0 g (71.4mmol) of dimethyl 2-(3-methoxy-2-methylbenzyl)malonate, there wasobtained 10.33 g (74.6% yield) of the product as a white solid, mp143-147° C. The structure was confirmed by NMR and mass spectroscopy. MSm/z 195 (M+H⁺).

Step 8: 3-(3-Methoxy-2-methylphenyl)-1-propanol

Following the procedure of Example 46, Step 4, but using 10.33 g (53.2mmol) of 3-(3-methoxy-2-methylphenyl)propanoic acid, there was obtained9.48 g (99% yield) of the product as a clear oil. The structure wasconfirmed by NMR and mass spectroscopy. MS m/z 181 (M+H⁺).

Step 9: 1-(3-Bromopropyl)-3-methoxy-2-methylbenzene

Following the procedure of Example 46, Step 5, but using 9.48 g (52.6mmol) of 3-(3-methoxy-2-methylphenyl)-1-propanol, there was obtained12.78 g (100% yield) of the product as an oil. The structure wasconfirmed by NMR spectroscopy.

Step 10: 3-(3-Methoxy-2-methylphenyl)propyl cyanide

Following the procedure of Example 46, Step 6, but using 12.78 g (52.6mmol) of 1-(3-bromopropyl)-3-methoxy-2-methylbenzene, there was obtained9.94 g (100% yield) of the product as an oil. The structure wasconfirmed by NMR and mass spectroscopy. MS m/z 190 (M+H⁺).

Step 11: 4-(3-Methoxy-2-methylphenyl)butanoic acid

Following the procedure of Example 46, Step 7, but using 9.94 g (52.5mmol) of 3-(3-methoxy-2-methylphenyl)propyl cyanide, there was obtained8.41 g (77% yield) of the product as a white solid, mp 105-107° C. Thestructure was confirmed by NMR and mass spectroscopy. MS m/z 209 (M+H⁺).

Step 12: 6-Methoxy-5-methyl-1,2,3,4-tetrahydro-1-naphthalenone

Following the procedure of Example 46, Step 8, but using 8.41 g (40.4mmol) of 4-(3-methoxy-2-methylphenyl)butanoic acid, there was obtained7.29 g (94.9% yield) of the product as a pink solid, mp 103-105° C. Thestructure was confirmed by No and mass spectroscopy. MS m/z 191 (M+H⁺).

Step 13: 6-Hydroxy-5-methyl-1,2,3,4-tetrahydro-1-naphthalenone

Following the procedure of Example 46, Step 9, but using 7.29 g (38.3mmol) of 6-methoxy-5-methyl-1,2,3,4-tetrahydro-1-napthalenone, there wasobtained 4.26 g (63.1% yield) of the product as a brown solid, mp195-197° C. The structure was confirmed by NMR and mass spectroscopy. MSm/z 177 (M+H⁺).

Step 14:6-[2-(1H-1-Imidazolyl)ethoxy]-5-methyl-1,2,3,4-tetrahydro-1-naphthalenone

Following the procedure of Example 46, Step 10, but using 4.26 g (24.4mmol) of 6-hydroxy-5-methyl-1,2,3,4-tetrahydro-1-naphthalenone, therewas obtained 3.13 g (47.9% yield) of the product as a pale, yellow oilwhich crystallized on standing. Trituration with hexane gave a whitesolid, mp 110-112° C. The structure was confirmed by No and massspectroscopy. MS m/z 271 (M+H⁺).

Calculated for C₁₆H₁₈N₂O₂×0.2 H₂O (MW 270.32): C, 70.15; H, 6.77; N,10.23. Found: C, 70.18; H, 6.55; N, 10.16.

EXAMPLE 486-[2-(1H-1-Imidazolyl)ethoxy]-5-methyl-2-[(E)-1-(2-thienyl)methylidene]-1,2,3,4-tetrahydro-1-naphthalenone

Following the procedure of Example 46, Step 11, but using 0.27 g (1.0mmol) of6-[2-(1H-1-imidazolyl)ethoxy]-5-methyl-1,2,3,4-tetrahydro-1-naphthalenone,there was obtained 227 mg (63.1% yield) of the product as a pale yellowsolid, mp 182-184° C. The structure was confirmed by NMR and massspectroscopy. MS m/z 365 (M+H⁺).

Calculated for C₂₁H₂₀N₂O₂S (MW 364.39): C, 69.22; H, 5.53; N, 7.69.Found: C, 69.04; H, 5.47; N, 7.62.

EXAMPLE 497-[2-(1H-1-Imidazolyl)ethoxy]-3-[(E)-1-(2-thienyl)methylidene]-1,2,3,4-tetrahydro-4-quinolinoneStep 1: 7-Hydroxy-1,2,3,4-tetrahydro-4-quinolinone

A solution of 1.1 g (6.2 mmol) of7-methoxy-1,2,3,4-tetrahydro-4-quinolinone (Rec. Trav. Chim.,1963;82:39) in 35 mL of CH₂Cl₂ was cooled in ice and treated with 5.0 mLof BBr₃. After stirring at 0° C. for 0.5 hour, the solution was allowedto stir at room temperature overnight. The solution was poured into icewater and made basic with 50% NaOH. After extracting with Et₂O, the pHwas brought to 5.5 with dilute HCl, and the solution extracted twicewith EtOAc. The EtOAc was washed with saturated NaCl and dried overMgSO₄. Removal of the solvent under reduced pressure gave 0.5 g (49.5%yield) of the product as an orange solid. The structure was confirmed byNMR and mass spectroscopy. MS m/z 164 (M+H⁺).

Step 2: 7-[2-(1H-1-Imidazolyl)ethoxy]-1,2,3,4-tetrahydro-4-quinolinone

Under N₂, a solution of 0.8 g (5.0 mmol) of7-hydroxy-1,2,3,4-tetrahydro-4-quinolinone in 20 mL of THF was treatedwith 0.62 g (5.5 mmol) of 2-(1H-1-imidazolyl)-1-ethanol and 1.13 (5.0mmol) of tripenylphosphine. The mixture was warmed to effect solution,then allowed to cool to room temperature. This was then treated over 10minutes with 0.8 mL (5.0 mmol) of diethyl azodicarboxylate. Some solidformed and the mixture was allowed to stir at room temperature for 3days. The mixture was diluted with EtOAc and filtered. The filtrate waswashed twice with H₂O, saturated NaHCO₃, then with saturated NaCl.Drying over MgSO4 and removal of the solvent under reduced pressure leftthe crude product. Chromatography on silica gel, eluting with CHCl₃/MeOH(90/10), gave 150 mg (11.8% yield) of the product as a golden oil. Thestructure was confirmed by mass spectroscopy. MS m/z 258 (M+H⁺).

Step 3:7-[2-(1H-1-Imidazolyl)ethoxy]-3-[(E)-1-(2-thienyl)methylidene]-1,2,3,4-tetrahydro-4-quinolinone

A solution of 0.15 g (0.6 mmol) of7-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-4-quinolinone in 2.0 mLof a 4% solution of KOH in EtOH was treated with 0.1 mL (0.8 mmol) of2-thiophenealdehyde and allowed to stir at room temperature overnight.The solution was diluted with H₂O and the precipitated solid collected.Resuspension in H₂O and filtering gave 60 mg (28.6% yield) of the pureproduct as a pink solid, mp 211-213° C. The structure was confirmed byNMR and mass spectroscopy. MS m/z 352 (M+H⁺).

Calculated for C₁₉H₁₇N₃O₂S.0.4 H₂O (MW 358.56): C, 63.64; H, 5.00; N,11.72. Found: C, 63.54; H. 4 83; N, 11.47.

EXAMPLE 50 7-[2-(1H-1-Imidazolyl)ethoxy]-4H-4-chromenone

Under N₂, a solution of 0.75 g (4.6 mmol) of 7-hydroxy-4H-4-chromenone(J. Med. Chem. 1991;34:248) in 20 mL of THF was treated with 1.21 g (4.6mmol) of triphenylphosphine and 0.5 g (5.1 mmol) of2-(1H-1-imidazolyl)-1-ethanol and the solution cooled in ice. This wasthen treated over 10 minutes with 0.72 mL (4.6 mmol) of diethylazodicarboxylate, and the solution stirred at room temperatureovernight. The solution was diluted with EtOAc, washed twice with H₂O,twice with saturated NaHCO₃, and then with saturated NaCl. Drying overMgSO₄ and removal of the solvent under reduced pressure gave the crudeproduct. Chromatography on silica gel, eluting with a gradient of CH₂Cl₂to CH₂Cl₂/MeOH (96/4) gave 0.12 g (10% yield) of the product as a pinksolid, mp 131-133° C. The structure was confirmed by NMR and massspectroscopy. MS m/z 257 (M+H⁺).

Calculated for C₁₄H₁₂N₂O₃×0.08 CH₂Cl₂ (MW 262.76): C, 64.34; H, 4.66; N,10.66. Found: C, 64.34; H, 4.72; N, 10.66.

EXAMPLE 51 7-[2-(1H-1-Imidazolyl)ethoxy]-4-chromanone

Under N₂, a solution of 2.0 g (0.012 mol) of 7-hydroxy-4-chromanone (J.Org. Chem., 1994;59:1216) in 25 mL of THF was treated with 1.29 g (0.013mol) of 2-(1H-1-imidazolyl)-1-ethanol and 3.15 g (0.012 mol) oftriphenylphosphine. The solution was cooled in ice and treated over 10minutes with a solution of 1.89 mL (0.012 mol) of diethylazodicarboxylate in 5.0 mL of THF. After stirring at room temperaturefor 3 days, the solution was diluted with EtOAc and washed withsaturated NaCl. Drying over MgSO₄ and removal of the solvent underreduced pressure left the crude product. Chromatography on silica gel,eluting with a gradient of CHCl₃ to CHCl₃/MeOH (96/4) gave the productwhich was recrystallized from EtOAc/hexane to give 0.92 g (29.7% yield)of a white solid, mp 128-130° C. The structure was confirmed by NMR andmass spectroscopy. MS m/z 259 (M+H⁺).

Calculated for C₁₄H₁₄N₂O₃ (MW 258.27): C, 65.11; H, 5.46; N, 10.85.Found: C, 64.76; H, 5.45; N, 10.71.

EXAMPLE 527-[2-(1H-1-Imidazolyl)ethoxy]-3-[(E)-1-(2-thienyl)methylidene]4-chromanone

A solution of 0.25 g (0.97 mmol) of7-[2-(1H-1-imidazolyl)ethoxy]-4-chromanone in 1.0 mL of HOAc containing0.1 mL of conc. H₂SO₄ was treated with 0.1 mL (0.97 mmol) of2-thiophenealdehyde and the solution stirred at room temperatureovernight. The solution was diluted with H₂O and washed with EtOAc. Theaqueous phase was made basic with dilute NaOH causing a solid toseparate. This was collected and dried giving 0.23 g (67.6% yield) ofthe product as a brown solid. The structure was confirmed by NMR andmass spectroscopy. MS m/z 353 (M+H⁺).

Calculated for C₁₉H₁₆N₂O₃S×0.3 H₂O (MW 357.74): C, 63.79; H, 4.68; N,7.83. Found: C, 63.73; H, 4.31; N, 7.65.

EXAMPLE 536-[2-(1H-1-Imidazolyl)ethoxyl]-1,2,3,4-tetrahydro-1-naphthalenone oxime

A solution of 1.0 g (3.9 mmol) of6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone in 10mL of pyridine was treated with 0.41 g (5.9 mmol) of hydroxylamine×HCland the solution heated at reflux overnight. The solution was dilutedwith H₂O and the product collected and dried. There was obtained 0.88 g(83% yield) of the product as a white solid, mp 177-179° C. Thestructure was confirmed by NMR and mass spectroscopy. MS m/z 272 (M+H⁺).

Calculated for C₁₅H₁₇N₃O₂ (MW 271.31): C, 66.40; H, 6.32; N, 15.49.Found: C, 66.06; H, 6.23; N, 15.41.

EXAMPLE 54[6-(2-Imidazol-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-ylideneaminooxy]-aceticacid

A solution of 1.0 g (3.9 mmol) of6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone in 10mL of pyridine was treated with 1.02 g (9.3 mmol) ofcarboxymethoxyamine×0.5 HCl and the solution heated at reflux for 2days. The solution was diluted with H₂O and extracted with EtOAc. Onstanding, the aqueous phase deposited a solid which was collected anddried. There was obtained 0.56 g (43% yield) of the product as a whitesolid, mp 193-195° C. The structure was confirmed by NMR and massspectroscopy. MS m/z 330 (M+H⁺).

Calculated for C₁₇H₁₉N₃O₄×0.2 H₂O (MW 332.95): C, 61.32; H, 5.87; N,12.62. Found: C, 61.38; H, 5.61; N, 12.63.

EXAMPLE 552-[6-(2-Imidazol-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-ylideneaminooxy]-N-(2-methyl-2-phenyl-propyl)-acetamide

A solution of 0.28 g (0.85 mmol) of[6-(2-imidazolyl-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-ylideneaminooxy]-aceticacid in 20 mL of EtOAc and 10 mL of DMF was treated with 0.13 g (9.3mmol) of HOBT and 0.17 g (9.3 mmol) of2-methyl-2-phenyl-1-propanamine×HCl. Et₃N (0.13 mL, 9.3 mmol) was thenadded followed by 0.19 g (9.3 mmol) of dicyclohexylcarbodiimide, and themixture stirred at room temperature for 3 days. The mixture was dilutedwith EtOAc, filtered, and the filtrate washed 3 times with H₂O, thentwice with saturated NaHCO₃, then with saturated NaCl. Drying over MgSO₄and removal of the solvent under reduced pressure gave the crudeproduct. Chromatography on silica gel, eluting with a gradient of CH₂Cl₂to CH₂Cl₂/MeOH (96/4) gave 0.34 g (87% yield) of the product as a whitesolid foam. The structure was confirmed by NMR and mass spectroscopy. MSm/z 461 (M+H⁺).

Calculated for C₂₇H₃₂N₄O₃×0.1 CH₂Cl₂ (MW 469.05): C, 69.39; H, 6.92; N,11.95. Found: C, 69.38; H, 6.99; N,11.67.

EXAMPLES 56-74

Examples 56-74 were prepared as part of a parallel synthesis array. Asolution of 0.15 g (0.59 mmol) of6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone in 2 mLof a 4% KOH in EtOH solution was treated with 0.95 equivalents of theappropriate aromatic aldehyde and shaken overnight. Those samples wherea solid was present were diluted with H₂O and the solid collected anddried. Those samples where a solution was present were mixed with 2 mLof CH₂Cl₂ and shaken. The CH₂Cl₂ layer was separated and dried in astream of N₂. The purity of the samples was determined by HPLC and thestructures confirmed by mass spectroscopy.

EXAMPLE 562-[(E)-1-(2-Chlorophenyl)methylidene]-6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone

MS m/z 379 (M+H⁺), purity 94.8%.

EXAMPLE 572-[(E)-1-(3-Chlorophenyl)methylidene]-6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone

MS m/z 379 (M+H⁺), purity 84.1%.

EXAMPLE 582-[(E)-1-(4-Chlorophenyl)methylidene]-6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone

MS m/z 379 (M+H⁺), purity 99.0%.

EXAMPLE 592-[(E)-1-(1,3-Benzodioxol-5-yl)methylidene]-6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone

MS m/z 389 (M+H⁺), purity 78.1%.

EXAMPLE 602-[(E)-1-(4-Fluorophenyl)methylidene]-6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone

MS m/z 363 (M+H⁺), purity 79.7%.

EXAMPLE 612-[(E)-1-(2,3-Dichlorophenyl)methylidene]-6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone

MS m/z 413 (M+H⁺), purity 90.1%.

EXAMPLE 622-[(E)-1-(2,6-Dichlorophenyl)methylidene]-6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone

MS m/z 413 (M+H⁺), purity 96.3%.

EXAMPLE 632-[(E)-1-(3,4-Dichlorophenyl)methylidene]-6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone

MS m/z 413 (M+H⁺), purity 99.4%.

EXAMPLE 642-[(E)-1-(3,5-Dichlorophenyl)methylidene]-6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4tetrahydro-1-naphthalenone

MS m/z 413 (M+H⁺), purity 52.9%.

EXAMPLE 652-[(E)-1(2,5-Dimethoxphenyl)methylidene]-6-[2-(1H1-imidazolylethoxy-]1,2,3,4tetrahydro-1-naphthalenone

MS m/z 405 (M+H⁺), purity 84.0%.

EXAMPLE 662-[(E)-1-(2,3-Dimethoxyphenyl)methylidene]-6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone

MS m/z 405 (M+H⁺), purity 84.2%.

EXAMPLE 676-[2-(1H-1-Imidazolyl)ethoxy]-2-(E)-1-[2-(trifluoromethyl)phenyl]methylidene-1,2,3,4-tetrahydro-1-naphthalenone

MS m/z 413 (M+H⁺), purity 71.3%

EXAMPLE 686-[2-(1H-1-Imidazolyl)ethoxy]-2-[(E)-1-(2,4,6-trimethoxyphenyl)methylidene]-1,2,3,4-tetrahydro-1-naphthalenone

MS m/z 435 (M+H⁺), purity 81.0%.

EXAMPLE 696-[2-(1H-1-Imidazolyl)ethoxy]-2-[(E)-1-(2,3,4-trimethoxyphenyl)methylidene]-1,2,3,4-tetrahydro-1-naphthalenone

MS m/z 435 (M+H⁺), purity 93.3%

EXAMPLE 706-[2-(1H-1-Imidazolyl)ethoxy]-2-[(E)-1-(4-iodophenyl)methylidene]-1,2,3,4-tetrahydro-1-naphthalenone

MS m/z 471 (M+H⁺), purity 96.1%.

EXAMPLE 712-(E)-1-[4-(Dimethylamino)phenyl]methylidene-6-[2-(1H-1-imidazolylethoxy]-1,2,3,4-tetrahydro-1-naphthalenone

MS m/z 388 (M+H⁺), purity 40.6%.

EXAMPLE 722-(E)-1-[4-(tert-Butyl)phenyl]methylidene-6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone

MS m/z 417 (M+H⁺), purity 100%.

EXAMPLE 736-[2-(1H-1-Imidazolyl)ethoxy]-2-[(E)-1-(3-methoxyphenyl)methylidene]-1,2,3,4-tetrahydro-1-naphthalenone

MS m/z 375 (M+H⁺), purity 87.8%.

EXAMPLE 746-[2-(1H-1-Imidazolyl)ethoxy]-2-[(E)-1-(3-methylphenyl)methylidene]-1,2,3,4-tetrahydro-1-naphthalenone

MS m/z 359 (M+H⁺), purity 86.5%.

EXAMPLE 752-(E)-1-[4-(Diethylamino)phenyl]methylidene-6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone,di-trifluoroacetic acid salt

A solution of 0.35 g (2.0 mmol) of 4-diethylaminobenzaldehyde and 0.26 g(1.0 mmol) of6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone in 1.0mL of a 4% solution of KOH in EtOH was heated at reflux overnight. Thesolution was diluted with EtOAc and washed with H₂O, then saturatedNaCl. Drying over MgSO₄ and removal of the solvent under pressure leftthe crude product. Chromatography on silica gel, eluting with a gradientof EtOAc to EtOAc/MeOH (96/4) gave 0.23 g of material of 86% purity.Preparative HPLC gave 60 mg of pure product isolated as thedi-trifluoroacetic acid salt. The structure was confirmed by NMR andmass spectroscopy. MS m/z 416 (M+H⁺).

Calculated for C₂₆H₂₉N₃O₂×2.3 C₂HO₂F₃×1.0 H₂O (MW 695.80): C, 52.82; H,4.82; N, 6.04. Found: C, 52.73; H, 4.47; N, 5.88.

EXAMPLE 76 7-[2-(1H-1-Imidazolyl)ethoxy]-2-phenyl-4-chromanone

A solution of 5.0 g (20.8 mmol) of 7-hydroxy-2-phenyl-4-chromanone in200 mL of THF was treated with 6.22 g (23.7 mmol) of triphenylphosphineand 2.65 g (23.7 mmol) of 2-(1H-1-imidazolyl)-1-ethanol. A solution of4.13 g (23.7 mmol) of diethyl azodicarboxylate in 25 mL of THF was addeddropwise and the solution allowed to stir at room temperature overnight.The solvent was removed under pressure, and the residue taken up in 1Ncitric acid and washed three times with Et₂O. The aqueous phase wasadjusted to pH 7 with 50% NaOH and extracted with EtOAc. The EtOAc waswashed with saturated NaCl and dried over MgSO₄. Treatment with charcoaland removal of the solvent under pressure gave 3.0 g (43% yield) of theproduct as a white solid, mp 139-140° C. The structure was confirmed byNMR and mass spectroscopy. MS m/z 335 (M+H⁺).

Calculated for C₂₀H₁₈N₂O₃ (MW 334.38): C, 71.84; H, 5.43; N, 8.38.Found: C, 71.60; H, 5.29; N, 8.31.

EXAMPLE 77 7-[2-(1H-1-Imidazolyl)ethoxy]-2-phenyl-4H-4-chromenone

Following the procedure of Example 76, but using 2.0 g (8.4 mmol) of7-hydroxy-2-phenyl-4H-4-chromenone, there was obtained 0.86 g (31%yield) of the product as a white solid, mp 155-159° C. The structure wasconfirmed by NMR and mass spectroscopy. MS m/z 333 (M+H⁺).

Calculated for C₂₀H₁₆N₂O₃ (MW 332.36): C, 72.28; H, 4.85; N, 8.43.Found: C, 72.07; H, 4.70; N, 8.36.

EXAMPLE 786-[2-(1H-1-Imidazolyl)propoxy]-1,2,3,4-tetrahydro-1-naphthalenone Step1: Ethyl 2-(1H-1-Imidazolyl)propanoate

A suspension of 16.0 g (0.4 mol) of NaH-oil (60%) was washed with hexaneto remove the oil and then resuspended in 400 mL of THF. This was thentreated dropwise with a solution of 27.23 g (0.4 mol) of imidazole in150 mL of THF and then refluxed for 1hour. This was then treateddropwise with a solution. of 72.4 g (0.4 mol) of ethyl 2-bromopropanoatein 100 mL of THF and the mixture heated at reflux for 2.5 hours. Themixture was filtered and the solvent removed under reduced pressure. Theresidue was taken up in Et₂O and washed with H₂O, then saturated NaCl.Drying over MgSO₄ and treatment with charcoal gave the crude product.This was triturated with pentane and the pentane removed under reducedpressure to give 38.56 g (57.3% yield) of the product as an oil. Thestructure was confirmed by NMR and mass spectroscopy. MS m/z 169 (M+H⁺).

Step 2: 2-(1H-1-Imidazolyl)-1-propanol

A suspension of 16.6 g (0.437 mol) of lithium aluminum hydride in 700 mLof THF was warmed to 40° C. and treated dropwise with 36.8 g (0.219 mol)of ethyl 2-(1H-1-imidazolyl)propanoate and the suspension allowed tostir at room temperature for 2.5 hours. The mixture was decomposed withdilute NaOH, filtered, and the solid washed with THF. The solvent wasremoved under reduced pressure and the residue distilled at 155-170°C./0.5 mm Hg. There was obtained 18.6 g (67% yield) of the product as anoil. The structure was confirmed by NMR and mass spectroscopy. MS m/z127 (M+H⁺).

Step 3:6-[2-(1H-1-Imidazolyl)propoxy]-1,2,3,4-tetrahydro-1-naphthalenone

Following the procedure of Example 76, but using 1.79 g (14.2 mmol) of2-(1H-1-imidazolyl)-1-propanol and 2.0 g (12.3 mmol) of6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone, therewas obtained 1.63 g (49% yield) of the product as a white solid, mp132-135° C. The structure was confirmed by NMR and mass spectroscopy. MSm/z 271 (M+H⁺).

Calculated for C₁₆H₁₈N₂O₂ (MW 270.34): C,71.09; H, 6.71; N, 10.36.Found: C, 70.71; H, 6.70; N, 10.20.

EXAMPLE 796-[2-(1H-1-Imidazolyl)propoxy]-2-[(E)-1-(2-thienyl)methylidene]-1,2,3,4-tetrahydro-1-naphthalenone

Following the procedure of Example 44, but using 0.73 g (2.7 mmol) of6-[2-(1H-1-imidazolyl)propoxy]-1,2,3,4-tetrahydro-1-naphthalenone, therewas obtained 0.62 g (98.2% yield) of the product as a pale yellow solid,mp 160-162° C. The structure was confirmed by NMR and mass spectroscopy.MS m/z 365 (M+H⁺).

Calculated for C₂₁H₂₀N₂O₂S (MW 364.47): C, 69.21; H, 5.53; N, 7.69; S,8.80. Found: C, 68.10; H, 5.31; N, 7.42; S, 8.53.

EXAMPLE 806-[2-(1H-1-Imidazolyl)-1-phenylethoxy]-1,2,3,4-tetrahydro-1-naphthalenoneStep1: 2-(1H-1-Imidazolyl)-1-phenyl-1-ethanol

A solution of 17.6 g (0. 2 58 mol) of imidazole in 100 mL of absoluteEtOH was treated with 0.6 mL (4.0 mmol) of pyridine and refluxed for 25minutes. This was then treated dropwise with a solution of 31.06 g(0.258 mol) of styrene oxide and the solution heated at refluxovernight. The solvent was removed under reduced pressure and theresidue taken up in Et₂O and washed with H₂O. A solid separated whichwas collected and dissolved in warm CHCl₃/EtOAc. The organic phase waswashed with saturated NaCl and dried over MgSO₄. Treatment of thefiltrate with charcoal, filtering, and concentrating to ⅓ volume causeda solid to separate. There was collected 17.09 g (35% yield) of theproduct as a white solid, mp 146-148° C. The structure was confirmed byNMR and mass spectroscopy. MS m/z 189 (M+H⁺).

Step 2:6-[2H-1-Imidazolyl)-1-phenylethoxy]-1,2,3,4-tetrahydro-1-naphthalenone

Following the procedure of Example 78, Step 3, but using 2.63 g (4.0mmol) of 2-(1H-1-imidazolyl)-1-phenyl-1-ethanol and 2.0 g (12.3 mmol) of6-[2-(1-H-1-imidazolyl)ethoxy]1,2,3,4-tetrahydro -1-naphthalenone, therewas obtained 3.83 g (93.6% yield) of the product as a glass. Thestructure was confirmed by NMR and mass spectroscopy. MS m/z 333 (M+H⁺).

EXAMPLE 816-(2-Imidazol-1-yl-1-phenyl-ethoxy)-2-thiophen-2-ylmethylene-3,4-dihydro-2H-naphthalen-1-one

Following the procedure of Example 46, Step 11, but using the product ofExample 80, there was obtained the product as yellow solid foam. Thestructure was confirmed by NMR and mass spectroscopy. MS m/z 427 (M+H⁺).

EXAMPLE 822-[6-(2-Imidazol-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-ylideneaminooxy]-N-(1-phenyl-cyclobutylmethyl)-acetamide

Following the procedure of Example 55 but using(1-phenylcyclobutyl)-methanamine, there was obtained the product as awhite solid foam. The structure was confirmed by NMR and massspectroscopy. MS m/z 473 (M+H⁺).

EXAMPLE 83 7-[2-(1H-Imidazolyl)ethoxy]-2,2-dimethyl-4-chromanone

Following the procedure of Example 30 but using7-hydroxy-2,2-dimethyl-4-chromanone and 1-(2-hydroxyethyl)imidazole,there was obtained the title compound as a solid, mp 84-86° C. Thestructure was confirmed by NMR and mass spectroscopy. MS m/z 287 (M+H⁺).

Calculated for C₁₆H₁₈N₂O₃ (MW 286.33): C, 67.12; H, 6.34; N, 9.78.Found: C, 67.00; H, 6.19; N, 9.72.

The data in the table below shows the farnesyl protein transferaseinhibitory activity of compounds of the present invention.

Example Number FTase, IC₅₀, μM 1 2.0 2 8.4 3 2.4 (n = 1) 4 0.078 5 1.37(n = 1) 6 1.26 7 1.7 (n = 1) 8 11.9 (n = 1) 9 0.24 10 0.37 11 0.12 (n =4) 12 0.60 13 0.29 14 0.089 15 1.3 16 0.11 17 0.1 18 0.32 19 0.70 20 3.121 2.8 22 0.37 23 1.6 24 0.88 25 2.5 27 1.79 (n = 3) 28 0.17 29 0.088 300.89 (n = 1) 31 0.59 32 9.1 33 7.3 (n = 1) 34 12.2 35 2.0 36 3.5 37 0.4938 4.3 39 3.1 40 4.7 41 0.19 42 5.9 43 4.4 44 3.6 45 5.8 46 15.4 47 1.348 0.4 50 2.6 51 4.4 52 0.22 53 3.0 54 0.34 55 0.60 56 0.36 57 0.42 580.17 59 0.21 60 0.18 61 0.57 62 0.54 63 0.89 64 0.57 65 0.63 66 1.84 670.71 68 0.59 69 1.30 70 0.32 71 0.11 72 1.20 73 1.14 74 1.89 76 0.12 779.3 78 2.6 79 0.23 80 0.073 81 0.037 82 0.42 83 0.90

In general, the IC₅₀ represents the average of two tests. If otherwise,the number of tests is given in parentheses after the IC₅₀ value. Forexample, n=4, means the average IC₅₀ value for four tests. Theactivities listed for Examples 56-74, which were prepared by a parallelsynthesis array, are the result of a single test. The values from thisarray have also been adjusted to account for the purity of the sample.

What is claimed is:
 1. A compound having the Formula I

wherein Q is O, —NOR, —N—NRR, —NOCH₂CO2R^(a),

L is hydrogen,

each R^(a) or R^(b) is independently hydrogen, C₁-C₆ alkyl, C₂C₆alkenyl, phenyl, or substituted phenyl, or R^(a) and R^(b) along withthe carbon atom to which they are bonded form a C₃-C₆ cycloalkyl ring;each R is independently hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, benzyl,C₂-C₆ alkenyl, phenyl, or substituted phenyl; Each - - - is a bond orabsent;

X is CH₂O, CH₂S, CH₂SO, CH₂SO₂, or CH₂NR; Z is hydrogen when L is

 and Z is —NRR, —R, —OR, —SR, (CH₂)_(n)E, —O(CH₂)_(n)E, —NR(CH₂)_(n)E,—S(CH₂)_(n)E, —N¹-piperidinyl, —N¹-piperazinyl[N⁴—R], —N-pyrrolidinyl,—N-morpholino, —N-thiomorpholino, —N-hexahydroazepine, or an amino acidhaving the structure

when L is

where A is a side chain of the amino acid glycine, alanine, valine,leucine, isoleucine, phenylalanine, proline, serine, threonine,tyrosine, asparagine, glutamine, lysine, arginine, tryptophan,histidine, cysteine, methionine, aspartic acid, or glutamic acid; E ishydrogen, halogen, —CO₂R, —CONRR, —CN, —NO₂, C₁-C₆ perfluoroalkyl, C₁-C₆perfluoroalkoxy, acetyl, —OR, —SR, —NRR, —N¹-piperidinyl,—N¹-piperazinyl[N⁴—R], —N-pyrrolidinyl, —N-morpholino,—N-thiomorpholino, —N-hexahydroazepine, aryl, heteroaryl, substitutedaryl, or substituted heteroaryl; each E′ is independently hydrogen,halogen, —NO₂, —NRR, —R, —OR,

each n is independently 0 to 5 inclusive; each α is independently 0, 1,or 2; each m is independently 0, 2, 3, 4, or 5; Y is CH₂, NR, O, SO,SO₂, or S; A′ is aryl, heteroaryl, substituted aryl, substitutedheteroaryl, C₁-C₆ alkyl, C₁-C₆ substituted alkyl,

 C₃-C₆ cycloalkyl or C₃-C₆ substituted cycloalkyl, provided anysubstituents are not —NO₂; B is pyrrolyl, substituted pyrrolyl,imidazolyl, substituted imidazolyl, oxazolyl, substituted oxazolyl,thiazolyl, substituted thiazolyl,

—NR¹—(CH₂)_(n)—(CHX³)—(CH₂)_(n)—SR¹, —S—(CH₂)_(n)—(CHX³)—(CH₂)_(n)—SR¹,or —(CH₂)_(n)—(CHX³)—(CH₂)_(n)—SR¹; X¹ is S or NR¹; X² is NR¹ or CH₂; R¹is hydrogen or C₁-C₆ alkyl; X³ is hydrogen —NR¹R¹ or —C₁-C₆ alkyl, andthe pharmaceutically acceptable salts, esters, amides, and prodrugsthereof, provided that the compound is not5-(2-imidazole-1-yl-ethoxy)-indan-1-one.
 2. A compound in accordancewith claim 1 wherein Q is O.
 3. A compound in accordance with claim 1wherein E′ is hydrogen.
 4. A compound in accordance with claim 1 whereinP is CH.
 5. A compound in accordance with claim 1 wherein Y is O.
 6. Acompound in accordance with claim 1 wherein L is hydrogen.
 7. A compoundin accordance with claim 1 wherein B is imidazolyl or substitutedimidazolyl.
 8. A compound in accordance with claim 1 wherein L is

Z is hydrogen; and A′ is phenyl, substituted phenyl, pyridyl,substituted pyridyl, thienyl, substituted thienyl, furyl, substitutedfuryl, naphthyl, or substituted naphthyl.
 9. The compounds:7-[2-(1H-1-Imidazolyl)ethoxy]-3-[(E)-1-(2-thienyl)methylidene]-1,2,3,4-tetrahydro-4-quinolinone;7-[2-(1H-1-Imidazolyl)ethoxy]-4H-4-chromenone;7-[2-(1H-1-Imidazolyl)ethoxy]-4-chromanone; and7-[2-(1H-1-Imidazolyl)ethoxy]-3-[(E)-1-(2-thienyl)methylidene]-4-chromanone.10. The compounds: 7-[2-(1H-1-Imidazolyl)ethoxy]-2-phenyl-chromanone;7-[2-(1H-1-Imidazolyl)ethoxy]-2-phenyl-4H-4-chromenone; and7-[2-(1H-Imidazolyl)ethoxy]-2,2-dimethyl-4-chromanone.
 11. Apharmaceutically acceptable composition that comprises a compound ofclaim
 1. 12. A method of treating or preventing restenosis oratherosclerosis, the method comprising administering to a patient havingrestenosis or atherosclerosis or at risk of having restenosis oratherosclerosis a therapeutically effective amount of a compound ofclaim
 1. 13. A method of treating cancer, the method comprisingadministering to a patient having cancer a therapeutically effectiveamount of a compound of claim
 1. 14. A method of treating or preventingrestenosis or atherosclerosis or treating cancer, the method ofcomprising administering to a patient having restenosis oratherosclerosis, or at risk of having restenosis or atherosclerosis, orhaving cancer a therapeutically effective amount of a compound ofFormula I

wherein Q is O, —NOR, —N—NRR, —NOCH₂CO₂R^(a),

L is hydrogen,

each R^(a) or R^(b) is independently hydrogen, C₁-C₆ alkyl, C₂-C₆alkenyl, phenyl, or substituted phenyl, or R^(a) and R^(b) along withthe carbon atom to which they are bonded form a C₃-C₆ cycloalkyl ring;each R is independently hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, benzyl,C₂-C₆ alkenyl, phenyl, or substituted phenyl; Each - - - is a bond orabsent;

X is CH₂O, CH₂S, CH₂SO, CH₂SO₂, or CH₂NR; Z is hydrogen when L is

 and Z is —NRR, —R, —OR, —SR, —(CH₂)_(n)E, —O(CH₂)_(n)E, —NR(CH₂)_(n)E,—S(CH₂)_(n)E, —N¹-piperidinyl, —N¹-piperazinyl[N⁴—R], —N-pyrrolidinyl,—N-morpholino, —N-thiomorpholino, —N-hexahydroazepine, or an amino acidhaving the structure

when L is

where A is a side chain of the amino acid glycine, alanine, valine,leucine, isoleucine, phenylalanine, proline, serine, threonine,tyrosine, asparagine, glutamine, lysine, arginine, tryptophan,histidine, cysteine, methionine, aspartic acid, or glutamic acid; E ishydrogen, halogen, —CO₂R, —CONRR, —CN, —NO₂, C₁-C₆ perfluoroalkyl, C₁-C₆perfluoroalkoxy, acetyl, —OR, —SR, —NRR, —N¹-piperidinyl,—N¹-piperazinyl[N⁴—R], —N-pyrrolidinyl, —N-morpholino,—N-thiomorpholino, —N-hexahydroazepine, aryl, heteroaryl, substitutedaryl, or substituted heteroaryl; each E′ is independently hydrogen,halogen, —NO₂, —NRR, —R, —OR,

each n is independently 0 to 5 inclusive; each α is independently 0, 1,or 2; each m is independently 0, 2, 3, 4, or 5; Y is CH₂, NR, O, SO,SO₂, or S; A′ is aryl, heteroaryl, substituted aryl, substitutedheteroaryl, C₁-C₆ alkyl, C₁-C₆ substituted alkyl,

 C₃-C₆ cycloalkyl or C₃-C₆ substituted cycloalkyl, provided anysubstituents are not —NO₂; B is pyrrolyl, substituted pyrrolyl,imidazolyl, substituted imidazolyl, oxazolyl, substituted oxazolyl,thiazolyl, substituted thiazolyl,

—NR¹—(CH₂)_(n)—(CHX³)—(CH₂)_(n)—SR¹, —S—(CH₂)_(n)—(CHX³)—(CH₂)_(n)—SR¹,or —(CH₂)_(n)—(CHX³)—(CH₂)_(n)—SR¹; X¹ is S or NR¹; X² is NR¹ or CH₂; R¹is hydrogen or C₁-C₆ alkyl; X³ is hydrogen —NR¹R¹ or —C₁-C₆ alkyl, andthe pharmaceutically acceptable salts, esters, amides, and prodrugsthereof.
 15. A compound having the Formula IV

wherein each J is independently C₁-C₆ alkyl; Y is CH₂, NR, O, SO, SO₂,or S; each m is independently 0, 2, 3, 4, or 5; each R^(a) or R^(b) isindependently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, phenyl, substitutedphenyl, or R^(a) and R^(b) together with the carbon atom to which theyare bonded form a C₃-C₆ cycloalkyl ring; B is pyrrolyl, substitutedpyrrolyl, imidazolyl, substituted imidazolyl, oxazolyl, substitutedoxazolyl, thiazolyl, substituted thiazolyl,

—NR¹—(CH₂)_(n)—(CHX³)—(CH₂)_(n)—SR¹, —S—(CH₂)_(n)—(CHX₃)—(CH₂)_(n)—SR¹,or —(CH₂)_(n)—(CHX³)—(CH₂)_(n)—SR¹; X¹ is S or NR¹; X² is NR¹ or CH₂; R¹is hydrogen or C₁-C₆ alkyl; X³ is hydrogen —NR¹R¹ or —C₁-C₆ alkyl; X is—O—; Q is O, —NOR, —N—NRR, —NOCH₂CO₂R^(a),

each R is independently hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, benzyl,C₂-C₆ alkenyl, phenyl, or substituted phenyl; each E′ is independentlyhydrogen, halogen, —NO₂, —NRR, —R, —OR,

each α is independently 0, 1, or 2; each n is independently 0 to 5; E ishydrogen, halogen, —CO₂R, —CONRR, —CN, —NO₂, C₁-C₆ perfluoroalkyl, C₁-C₆perfluoroalkoxy, acetyl, —OR, —SR, —NRR, —N¹-piperidinyl,—N¹-piperazinyl[N⁴—R], —N-pyrrolidinyl, —N-morpholino,—N-thiomorpholino, —N-hexahydroazepine, aryl, heteroaryl, substitutedaryl, or substituted heteroaryl; and the pharmaceutically acceptablesalts, esters, amides, and prodrugs thereof.
 16. A pharmaceuticallyacceptable composition that comprises a compound of claim
 15. 17. Amethod of treating or preventing restenosis or atherosclerosis, themethod comprising administering to a patient having restenosis oratherosclerosis or at risk of having restenosis or atherosclerosis atherapeutically effective amount of a compound of claim
 15. 18. A methodof treating cancer, the method comprising administering to a patienthaving cancer a therapeutically effective amount of a compound of claim15.